Enantioselective synthesis of alpha-quaternary mannich adducts by palladium-catalyzed allylic alkylation

ABSTRACT

with a transition metal catalyst under alkylation conditions.

RELATED APPLICATIONS

This Application is a Continuation of U.S. patent application Ser. No.14/972,475, filed Dec. 17, 2015, which claims the benefit of U.S.Provisional Application 62/093,982, filed Dec. 18, 2014, the contents ofboth of which are incorporated herein by reference.

GOVERNMENT SUPPORT

This invention was made with Government support under Grant NumberR01GM080269, awarded by the National Institutes of Health. TheGovernment has certain rights in the invention.

BACKGROUND OF THE INVENTION

The Mannich reaction, first discovered in the early 20th century, isamong the most robust reactions known to produce nitrogen-containingcompounds. In a classic intermolecular Mannich reaction, an aldehyde, anamine and an α-acidic carbonyl compound react to form a β-amino carbonylcompound. Recent progress in this area, including modified imine donorsand well-explored catalyst systems, has made available a wide variety ofasymmetric α-functionalizations of carbonyl compounds. However, to date,asymmetric Mannich-type reactions to establish α-quaternary carbonylcompounds have been limited to specialized substrate classes.

There exists a need for methods that enable access to α-quaternaryMannich Adducts, particularly enantioselective methods to provideenantioenriched products.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides methods for preparing acompound of formula (I):

comprising treating a compound of formula (II):

with a transition metal catalyst under alkylation conditions, wherein,as valence and stability permit,

-   R^(1a) and R^(1b) each independently represent hydrogen or    optionally substituted alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl,    aralkyl, heteroaryl, heteroaralkyl, alkenyl, alkynyl, —C(O)alkyl,    —C(O)aryl, —C(O)aralkyl, —C(O)heteroaryl, —C(O)heteroaralkyl,    —C(O)O(alkyl), —C(O)O(aryl), —C(O)O(aralkyl), —C(O)O(heteroaryl),    —C(O)O(heteroaralkyl), —S(O)₂(aryl), —S(O)₂(alkyl),    —S(O)₂(haloalkyl), —OR¹⁴, —SR¹⁴, or —NR¹⁴R¹⁵;-   R² and R³ each independently represent hydrogen or substituted or    unsubstituted alkyl, aralkyl, aryl, heteroaralkyl, heteroaryl,    (cycloalkyl)alkyl, cycloalkyl, (heterocycloalkyl)alkyl,    heterocycloalkyl, alkenyl, alkynyl, alkylamino, hydroxyalkyl,    alkoxyalkyl, aminoalkyl, or thioalkyl;-   or wherein R^(1a) and R² are taken together with the intervening    atoms to form an optionally substituted heterocyclic ring;-   R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, and R¹¹ are each independently selected    for each occurrence from hydrogen, hydroxyl, halogen, nitro, alkyl,    alkenyl, alkynyl, cyano, carboxyl, sulfate, amino, alkoxy,    alkylamino, alkylthio, hydroxyalkyl, alkoxyalkyl, aminoalkyl,    thioalkyl, ether, thioether, ester, amide, thioester, carbonate,    carbamate, urea, sulfonate, sulfone, sulfoxide, sulfonamide, acyl,    acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocycloalkyl,    aralkyl, arylalkoxy, heteroaralkyl, (cycloalkyl)alkyl, and    (heterocycloalkyl)alkyl;-   W¹ and W² are each independently selected from alkyl, alkenyl,    alkynyl, OR¹², SR¹², or NR¹²R¹³; or W¹ and W², taken together with    the intervening atoms, form an optionally substituted    heterocycloalkyl, cycloalkyl, heterocycloalkenyl, or cycloalkenyl    group;-   R¹² and R¹³ are independently selected for each occurrence from    hydrogen or substituted or unsubstituted alkyl, aralkyl, aryl,    heteroaralkyl, heteroaryl, (cycloalkyl)alkyl, cycloalkyl,    (heterocycloalkyl)alkyl, heterocycloalkyl, alkenyl, alkynyl,    hydroxyalkyl, alkoxyalkyl, aminoalkyl, and thioalkyl; and-   R¹⁴ and R¹⁵ are independently selected for each occurrence from    hydrogen or substituted or unsubstituted alkyl, aralkyl, aryl,    heteroaralkyl, heteroaryl, (cycloalkyl)alkyl, cycloalkyl,    (heterocycloalkyl)alkyl, heterocycloalkyl, alkenyl, and alkynyl.

In another aspect, the present invention provides an α-quaternaryMannich type product having the structure of formula (I),

or a salt thereof;wherein:

-   R^(1a) and R^(1b) each independently represent hydrogen or    optionally substituted alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl,    aralkyl, heteroaryl, heteroaralkyl, alkenyl, alkynyl, —C(O)alkyl,    —C(O)aryl, —C(O)aralkyl, —C(O)heteroaryl, —C(O)heteroaralkyl,    —C(O)O(alkyl), —C(O)O(aryl), —C(O)O(aralkyl), —C(O)O(heteroaryl),    —C(O)O(heteroaralkyl), —S(O)₂(aryl), —S(O)₂(alkyl),    —S(O)₂(haloalkyl), —OR¹⁴, —SR¹⁴, or —NR¹⁴R¹⁵;-   R² and R³ each independently represent hydrogen or substituted or    unsubstituted alkyl, aralkyl, aryl, heteroaralkyl, heteroaryl,    (cycloalkyl)alkyl, cycloalkyl, (heterocycloalkyl)alkyl,    heterocycloalkyl, alkenyl, alkynyl, alkylamino, hydroxyalkyl,    alkoxyalkyl, aminoalkyl, or thioalkyl;-   or wherein R^(1a) and R² are taken together with the intervening    atoms to form an optionally substituted heterocyclic ring;-   R⁸, R⁹, R¹⁰, and R¹¹ are independently selected for each occurrence    from hydrogen, hydroxyl, halogen, nitro, alkyl, alkenyl, alkynyl,    cyano, carboxyl, sulfate, amino, alkoxy, alkylamino, alkylthio,    hydroxyalkyl, alkoxyalkyl, aminoalkyl, thioalkyl, ether, thioether,    ester, amide, thioester, carbonate, carbamate, urea, sulfonate,    sulfone, sulfoxide, sulfonamide, acyl, acyloxy, acylamino, aryl,    heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl, arylalkoxy,    heteroaralkyl, (cycloalkyl)alkyl, and (heterocycloalkyl)alkyl;-   W¹ and W² are each independently selected from alkyl, alkenyl,    alkynyl, OR¹², SR¹², or NR¹²R¹³; or W¹ and W², taken together with    the intervening atoms, form an optionally substituted    heterocycloalkyl, cycloalkyl, heterocycloalkenyl, or cycloalkenyl    group;-   R¹² and R¹³ are independently selected for each occurrence from    hydrogen or substituted or unsubstituted alkyl, aralkyl, aryl,    heteroaralkyl, heteroaryl, (cycloalkyl)alkyl, cycloalkyl,    (heterocycloalkyl)alkyl, heterocycloalkyl, alkenyl, alkynyl,    hydroxyalkyl, alkoxyalkyl, aminoalkyl, and thioalkyl; and-   R¹⁴ and R¹⁵ are independently selected for each occurrence from    hydrogen or substituted or unsubstituted alkyl, aralkyl, aryl,    heteroaralkyl, heteroaryl, (cycloalkyl)alkyl, cycloalkyl,    (heterocycloalkyl)alkyl, heterocycloalkyl, alkenyl, and alkynyl.

In another aspect, the present invention provides a compound having thestructure of formula (II),

or a salt thereof;wherein:

-   R^(1a) and R^(1b) each independently represent hydrogen or    optionally substituted alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl,    aralkyl, heteroaryl, heteroaralkyl, alkenyl, alkynyl, —C(O)alkyl,    —C(O)aryl, —C(O)aralkyl, —C(O)heteroaryl, —C(O)heteroaralkyl,    —C(O)O(alkyl), —C(O)O(aryl), —C(O)O(aralkyl), —C(O)O(heteroaryl),    —C(O)O(heteroaralkyl), —S(O)₂(aryl), —S(O)₂(alkyl),    —S(O)₂(haloalkyl), —OR¹⁴, —SR¹⁴, or —NR¹⁴R¹⁵;-   R² and R³ each independently represent hydrogen or substituted or    unsubstituted alkyl, aralkyl, aryl, heteroaralkyl, heteroaryl,    (cycloalkyl)alkyl, cycloalkyl, (heterocycloalkyl)alkyl,    heterocycloalkyl, alkenyl, alkynyl, alkylamino, hydroxyalkyl,    alkoxyalkyl, aminoalkyl, or thioalkyl;-   or wherein R^(1a) and R² are taken together with the intervening    atoms to form an optionally substituted heterocyclic ring;-   R⁴, R⁵, R⁶, and R⁷ are independently selected for each occurrence    from hydrogen, hydroxyl, halogen, nitro, alkyl, alkenyl, alkynyl,    cyano, carboxyl, sulfate, amino, alkoxy, alkylamino, alkylthio,    hydroxyalkyl, alkoxyalkyl, aminoalkyl, thioalkyl, ether, thioether,    ester, amide, thioester, carbonate, carbamate, urea, sulfonate,    sulfone, sulfoxide, sulfonamide, acyl, acyloxy, acylamino, aryl,    heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl, arylalkoxy,    heteroaralkyl, (cycloalkyl)alkyl, and (heterocycloalkyl)alkyl;-   W¹ and W² are each independently selected from alkyl, alkenyl,    alkynyl, OR¹², SR¹², or NR¹²R¹³; or W¹ and W², taken together with    the intervening atoms, form an optionally substituted    heterocycloalkyl, cycloalkyl, heterocycloalkenyl, or cycloalkenyl    group;-   R¹² and R¹³ are independently selected for each occurrence from    hydrogen or substituted or unsubstituted alkyl, aralkyl, aryl,    heteroaralkyl, heteroaryl, (cycloalkyl)alkyl, cycloalkyl,    (heterocycloalkyl)alkyl, heterocycloalkyl, alkenyl, alkynyl,    hydroxyalkyl, alkoxyalkyl, aminoalkyl, and thioalkyl; and-   R¹⁴ and R¹⁵ are independently selected for each occurrence from    hydrogen or substituted or unsubstituted alkyl, aralkyl, aryl,    heteroaralkyl, heteroaryl, (cycloalkyl)alkyl, cycloalkyl,    (heterocycloalkyl)alkyl, heterocycloalkyl, alkenyl, and alkynyl.

DETAILED DESCRIPTION OF THE INVENTION I. Definitions

The definitions for the terms described below are applicable to the useof the term by itself or in combination with another term.

The term “acyl” is art-recognized and refers to a group represented bythe general formula hydrocarbyl-C(O)—, preferably alkyl-C(O)—.

The term “acylamino” is art-recognized and refers to an amino groupsubstituted with an acyl group and may be represented, for example, bythe formula hydrocarbyl-C(O)NH—.

The term “acyloxy” is art-recognized and refers to a group representedby the general formula hydrocarbylC(O)O—, preferably alkylC(O)O—.

The term “alkoxy” refers to an alkyl group, preferably a lower alkylgroup, having an oxygen attached thereto. Representative alkoxy groupsinclude methoxy, ethoxy, propoxy, tert-butoxy and the like.

The term “alkoxyalkyl” refers to an alkyl group substituted with analkoxy group and may be represented by the general formulaalkyl-O-alkyl.

The term “alkenyl”, as used herein, refers to an aliphatic groupcontaining at least one double bond that is straight chained or branchedand has from 1 to about 20 carbon atoms, preferably from 1 to about 10unless otherwise defined. The term “alkenyl” is intended to include both“unsubstituted alkenyls” and “substituted alkenyls”, the latter of whichrefers to alkenyl moieties having substituents replacing a hydrogen onone or more carbons of the alkenyl group. Such substituents may occur onone or more carbons that are included or not included in one or moredouble bonds. Moreover, such substituents include all those contemplatedfor alkyl groups, as discussed below, except where stability isprohibitive. For example, substitution of alkenyl groups by one or morealkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups iscontemplated.

An “alkyl” group or “alkane” is a straight chained or branchednon-aromatic hydrocarbon which is completely saturated. Typically, astraight chained or branched alkyl group has from 1 to about 20 carbonatoms, preferably from 1 to about 10 unless otherwise defined. Examplesof straight chained and branched alkyl groups include methyl, ethyl,n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl,pentyl and octyl. A C₁-C₆ straight chained or branched alkyl group isalso referred to as a “lower alkyl” group.

Moreover, the term “alkyl” (or “lower alkyl”) as used throughout thespecification, examples, and claims is intended to include both“unsubstituted alkyls” and “substituted alkyls”, the latter of whichrefers to alkyl moieties having substituents replacing a hydrogen on oneor more carbons of the hydrocarbon backbone. Such substituents, if nototherwise specified, can include, for example, a halogen, a hydroxyl, acarbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acylsuch as an alkylC(O)), a thiocarbonyl (such as a thioester, athioacetate, or a thioformate), an alkoxyl, a phosphoryl, a phosphate, aphosphonate, a phosphinate, an amino, an amido, an amidine, an imine, acyano, a nitro, an azido, a silyl ether, a sulfhydryl, an alkylthio, asulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, aheterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety. Itwill be understood by those skilled in the art that the moietiessubstituted on the hydrocarbon chain can themselves be substituted, ifappropriate. For instance, the substituents of a substituted alkyl mayinclude substituted and unsubstituted forms of amino, azido, imino,amido, phosphoryl (including phosphonate and phosphinate), sulfonyl(including sulfate, sulfonamido, sulfamoyl and sulfonate), and silylgroups, as well as ethers, alkylthiols, carbonyls (including ketones,aldehydes, carboxylates, and esters), —CF₃, —CN and the like. Exemplarysubstituted alkyls are described below. Cycloalkyls can be furthersubstituted with alkyls, alkenyls, alkoxys, alkylthios, aminoalkyls,carbonyl-substituted alkyls, —CF₃, —CN, and the like.

The term “C_(x-y)” when used in conjunction with a chemical moiety, suchas, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant toinclude groups that contain from x to y carbons in the chain. Forexample, the term “C_(x-y)alkyl” refers to substituted or unsubstitutedsaturated hydrocarbon groups, including straight-chain alkyl andbranched-chain alkyl groups that contain from x to y carbons in thechain, including haloalkyl groups such as trifluoromethyl and2,2,2-tirfluoroethyl, etc. C₀ alkyl indicates a hydrogen where the groupis in a terminal position, a bond if internal. The terms“C_(2-y)alkenyl” and “C_(2-y)alkynyl” refer to substituted orunsubstituted unsaturated aliphatic groups analogous in length andpossible substitution to the alkyls described above, but that contain atleast one double or triple bond respectively.

The term “alkylamino”, as used herein, refers to an amino groupsubstituted with at least one alkyl group.

The term “alkylthio”, as used herein, refers to a thiol groupsubstituted with an alkyl group and may be represented by the generalformula alkyl-S—.

The term “alkynyl”, as used herein, refers to an aliphatic groupcontaining at least one triple bond and is intended to include both“unsubstituted alkynyls” and “substituted alkynyls”, the latter of whichrefers to alkynyl moieties having substituents replacing a hydrogen onone or more carbons of the alkynyl group. Such substituents may occur onone or more carbons that are included or not included in one or moretriple bonds. Moreover, such substituents include all those contemplatedfor alkyl groups, as discussed above, except where stability isprohibitive. For example, substitution of alkynyl groups by one or morealkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups iscontemplated.

The term “amide”, as used herein, refers to a group

wherein each R¹⁰ independently represent a hydrogen or hydrocarbylgroup, or two R¹⁰ are taken together with the N atom to which they areattached complete a heterocycle having from 4 to 8 atoms in the ringstructure.

The terms “amine” and “amino” are art-recognized and refer to bothunsubstituted and substituted amines and salts thereof, e.g., a moietythat can be represented by

wherein each R¹⁰ independently represents a hydrogen or a hydrocarbylgroup, or two R¹⁰ are taken together with the N atom to which they areattached complete a heterocycle having from 4 to 8 atoms in the ringstructure.

The term “aminoalkyl”, as used herein, refers to an alkyl groupsubstituted with an amino group.

The term “aralkyl”, as used herein, refers to an alkyl group substitutedwith an aryl group. An aralkyl group is connected to the rest of themolecule through the alkyl component of the aralkyl group.

The term “aryl” as used herein include substituted or unsubstitutedsingle-ring aromatic groups in which each atom of the ring is carbon.Preferably the ring is a 5- to 10-membered ring, more preferably a 6- to10-membered ring or a 6-membered ring. The term “aryl” also includespolycyclic ring systems having two or more cyclic rings in which two ormore carbons are common to two adjoining rings wherein at least one ofthe rings is aromatic, e.g., the other cyclic rings can be cycloalkyls,cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.Aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline,and the like. Exemplary substitution on an aryl group can include, forexample, a halogen, a haloalkyl such as trifluoromethyl, a hydroxyl, acarbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acylsuch as an alkylC(O)), a thiocarbonyl (such as a thioester, athioacetate, or a thioformate), an alkoxyl, a phosphoryl, a phosphate, aphosphonate, a phosphinate, an amino, an amido, an amidine, an imine, acyano, a nitro, an azido, a silyl ether, a sulfhydryl, an alkylthio, asulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, aheterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety

The term “carbamate” is art-recognized and refers to a group

wherein R⁹ and R¹⁰ independently represent hydrogen or a hydrocarbylgroup, such as an alkyl group, or R⁹ and R¹⁰ taken together with theintervening atom(s) complete a heterocycle having from 4 to 8 atoms inthe ring structure.

The terms “carbocycle”, and “carbocyclic”, as used herein, refers to asaturated or unsaturated ring in which each atom of the ring is carbon.The term carbocycle includes both aromatic carbocycles and non-aromaticcarbocycles. Non-aromatic carbocycles include both cycloalkane rings, inwhich all carbon atoms are saturated, and cycloalkene rings, whichcontain at least one double bond. “Carbocycle” includes 5-7 memberedmonocyclic and 8-12 membered bicyclic rings. Each ring of a bicycliccarbocycle may be selected from saturated, unsaturated and aromaticrings. Carbocycle includes bicyclic molecules in which one, two or threeor more atoms are shared between the two rings. The term “fusedcarbocycle” refers to a bicyclic carbocycle in which each of the ringsshares two adjacent atoms with the other ring. Each ring of a fusedcarbocycle may be selected from saturated, unsaturated and aromaticrings. In an exemplary embodiment, an aromatic ring, e.g., phenyl, maybe fused to a saturated or unsaturated ring, e.g., cyclohexane,cyclopentane, or cyclohexene. Any combination of saturated, unsaturatedand aromatic bicyclic rings, as valence permits, is included in thedefinition of carbocyclic. Exemplary “carbocycles” include cyclopentane,cyclohexane, bicyclo[2.2.1]heptane, 1,5-cyclooctadiene,1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]oct-3-ene, naphthalene andadamantane. Exemplary fused carbocycles include decalin, naphthalene,1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]octane,4,5,6,7-tetrahydro-1H-indene and bicyclo[4.1.0]hept-3-ene. “Carbocycles”may be substituted at any one or more positions capable of bearing ahydrogen atom.

A “cycloalkyl” group is a cyclic hydrocarbon which is completelysaturated. “Cycloalkyl” includes monocyclic and bicyclic rings.Typically, a monocyclic cycloalkyl group has from 3 to about 10 carbonatoms, more typically 3 to 8 carbon atoms unless otherwise defined. Thesecond ring of a bicyclic cycloalkyl may be selected from saturated,unsaturated and aromatic rings. Cycloalkyl includes bicyclic moleculesin which one, two or three or more atoms are shared between the tworings. The term “fused cycloalkyl” refers to a bicyclic cycloalkyl inwhich each of the rings shares two adjacent atoms with the other ring.The second ring of a fused bicyclic cycloalkyl may be selected fromsaturated, unsaturated and aromatic rings. A “cycloalkenyl” group is acyclic hydrocarbon containing one or more double bonds.

The term “carbocyclylalkyl”, as used herein, refers to an alkyl groupsubstituted with a carbocycle group.

The term “carbonate” is art-recognized and refers to a group —OCO₂—R¹⁰,wherein R¹⁰ represents a hydrocarbyl group.

The term “carboxyl”, as used herein, refers to a group represented bythe formula —CO₂H.

The term “ester”, as used herein, refers to a group —C(O)OR¹⁰ whereinR¹⁰ represents a hydrocarbyl group.

The term “ether”, as used herein, refers to a hydrocarbyl group linkedthrough an oxygen to another hydrocarbyl group. Accordingly, an ethersubstituent of a hydrocarbyl group may be hydrocarbyl-O—. Ethers may beeither symmetrical or unsymmetrical. Examples of ethers include, but arenot limited to, heterocycle-O-heterocycle and aryl-O-heterocycle. Ethersinclude “alkoxyalkyl” groups, which may be represented by the generalformula alkyl-O-alkyl.

The terms “halo” and “halogen” as used herein means halogen and includeschloro, fluoro, bromo, and iodo.

The terms “hetaralkyl” and “heteroaralkyl”, as used herein, refers to analkyl group substituted with a heteroaryl group.

The term “heteroalkyl”, as used herein, refers to a saturated orunsaturated chain of carbon atoms and at least one heteroatom, whereinno two heteroatoms are adjacent.

The terms “heteroaryl” and “hetaryl” include substituted orunsubstituted aromatic single ring structures, preferably 5- to7-membered rings, more preferably 5- to 6-membered rings, whose ringstructures include at least one heteroatom, preferably one to fourheteroatoms, more preferably one or two heteroatoms. The terms“heteroaryl” and “hetaryl” also include polycyclic ring systems havingtwo or more cyclic rings in which two or more carbons are common to twoadjoining rings wherein at least one of the rings is heteroaromatic,e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls,cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls. Heteroarylgroups include 5- to 10-membered cyclic or polycyclic ring systems,including, for example, pyrrole, furan, thiophene, imidazole, oxazole,thiazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine, andthe like. Exemplary optional substituents on heteroaryl groups includethose substituents put forth as exemplary substituents on aryl groups,above.

The term “heteroatom” as used herein means an atom of any element otherthan carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, andsulfur.

The terms “heterocyclyl”, “heterocycle”, and “heterocyclic” refer tosubstituted or unsubstituted non-aromatic ring structures, preferably 3-to 10-membered rings, more preferably 3- to 7-membered rings, whose ringstructures include at least one heteroatom, preferably one to fourheteroatoms, more preferably one or two heteroatoms. The terms“heterocyclyl” and “heterocyclic” also include polycyclic ring systemshaving two or more cyclic rings in which two or more carbons are commonto two adjoining rings wherein at least one of the rings isheterocyclic, e.g., the other cyclic rings can be cycloalkyls,cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.Heterocyclyl groups include, for example, piperidine, piperazine,pyrrolidine, morpholine, lactones, lactams, and the like.

The term “heterocyclylalkyl”, as used herein, refers to an alkyl groupsubstituted with a heterocycle group.

The term “hydrocarbyl”, as used herein, refers to a group that is bondedthrough a carbon atom that does not have a —O or —S substituent, andtypically has at least one carbon-hydrogen bond and a primarily carbonbackbone, but may optionally include heteroatoms. Thus, groups likemethyl, ethoxyethyl, 2-pyridyl, and trifluoromethyl are considered to behydrocarbyl for the purposes of this application, but substituents suchas acetyl (which has a ═O substituent on the linking carbon) and ethoxy(which is linked through oxygen, not carbon) are not. Hydrocarbyl groupsinclude, but are not limited to aryl, heteroaryl, carbocycle,heterocyclyl, alkyl, alkenyl, alkynyl, and combinations thereof.

The term “hydroxyalkyl”, as used herein, refers to an alkyl groupsubstituted with a hydroxy group.

The term “lower” when used in conjunction with a chemical moiety, suchas, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant toinclude groups where there are ten or fewer non-hydrogen atoms in thesubstituent, preferably six or fewer. A “lower alkyl”, for example,refers to an alkyl group that contains ten or fewer carbon atoms,preferably six or fewer. In certain embodiments, acyl, acyloxy, alkyl,alkenyl, alkynyl, or alkoxy substituents defined herein are respectivelylower acyl, lower acyloxy, lower alkyl, lower alkenyl, lower alkynyl, orlower alkoxy, whether they appear alone or in combination with othersubstituents, such as in the recitations hydroxyalkyl and aralkyl (inwhich case, for example, the atoms within the aryl group are not countedwhen counting the carbon atoms in the alkyl substituent).

The terms “polycyclyl”, “polycycle”, and “polycyclic” refer to two ormore rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls,heteroaryls, and/or heterocyclyls) in which two or more atoms are commonto two adjoining rings, e.g., the rings are “fused rings”. Each of therings of the polycycle can be substituted or unsubstituted. In certainembodiments, each ring of the polycycle contains from 3 to 10 atoms inthe ring, preferably from 5 to 7.

The term “silyl” refers to a silicon moiety with three hydrocarbylmoieties attached thereto. A “silyl ether” refers to a silyl grouplinked through an oxygen to a hydrocarbyl group. Exemplary silyl ethersinclude —OSi(CH₃)₃ (—OTMS), —OSi(CH₃)₂t-Bu (—OTBS), —OSi(Ph)₂t-Bu(—OTBDPS), and —OSi(iPr)₃ (—OTIPS).

The term “substituted” refers to moieties having substituents replacinga hydrogen on one or more carbons of the backbone. It will be understoodthat “substitution” or “substituted with” includes the implicit provisothat such substitution is in accordance with permitted valence of thesubstituted atom and the substituent, and that the substitution resultsin a stable compound, e.g., which does not spontaneously undergotransformation such as by rearrangement, cyclization, elimination, etc.As used herein, the term “substituted” is contemplated to include allpermissible substituents of organic compounds. In a broad aspect, thepermissible substituents include acyclic and cyclic, branched andunbranched, carbocyclic and heterocyclic, aromatic and non-aromaticsubstituents of organic compounds. The permissible substituents can beone or more and the same or different for appropriate organic compounds.For purposes of this invention, the heteroatoms such as nitrogen mayhave hydrogen substituents and/or any permissible substituents oforganic compounds described herein which satisfy the valences of theheteroatoms. Substituents can include any substituents described herein,for example, a halogen, a haloalkyl, a hydroxyl, a carbonyl (such as acarboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (suchas a thioester, a thioacetate, or a thioformate), an alkoxyl, aphosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, anamido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl,an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, asulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromaticmoiety. It will be understood by those skilled in the art thatsubstituents can themselves be substituted, if appropriate. Unlessspecifically stated as “unsubstituted,” references to chemical moietiesherein are understood to include substituted variants. For example,reference to an “aryl” group or moiety implicitly includes bothsubstituted and unsubstituted variants.

The term “sulfate” is art-recognized and refers to the group —OSO₃H, ora pharmaceutically acceptable salt thereof.

The term “sulfonamide” is art-recognized and refers to the grouprepresented by the general formulae

wherein R⁹ and R¹⁰ independently represents hydrogen or hydrocarbyl,such as alkyl, or R⁹ and R¹⁰ taken together with the intervening atom(s)complete a heterocycle having from 4 to 8 atoms in the ring structure.

The term “sulfoxide” is art-recognized and refers to the group—S(O)—R¹⁰, wherein R¹⁰ represents a hydrocarbyl.

The term “sulfonate” is art-recognized and refers to the group SO₃H, ora pharmaceutically acceptable salt thereof.

The term “sulfone” is art-recognized and refers to the group —S(O)₂—R¹⁰,wherein R¹⁰ represents a hydrocarbyl.

The term “thioalkyl”, as used herein, refers to an alkyl groupsubstituted with a thiol group.

The term “thioester”, as used herein, refers to a group —C(O)SR¹⁰ or—SC(O)R¹⁰ wherein R¹⁰ represents a hydrocarbyl.

The term “thioether”, as used herein, is equivalent to an ether, whereinthe oxygen is replaced with a sulfur.

The term “urea” is art-recognized and may be represented by the generalformula

wherein R⁹ and R¹⁰ independently represent hydrogen or a hydrocarbyl,such as alkyl, or either occurrence of R⁹ taken together with R¹⁰ andthe intervening atom(s) complete a heterocycle having from 4 to 8 atomsin the ring structure.

“Protecting group” refers to a group of atoms that, when attached to areactive functional group in a molecule, mask, reduce or prevent thereactivity of the functional group. Typically, a protecting group may beselectively removed as desired during the course of a synthesis.Examples of protecting groups can be found in Greene and Wuts,Protective Groups in Organic Chemistry, 3^(rd) Ed., 1999, John Wiley &Sons, NY and Harrison et al., Compendium of Synthetic Organic Methods,Vols. 1-8, 1971-1996, John Wiley & Sons, NY. Representative nitrogenprotecting groups include, but are not limited to, formyl, acetyl,trifluoroacetyl, benzyl, benzyloxycarbonyl (“CBZ”), tert-butoxycarbonyl(“Boc”), trimethylsilyl (“TMS”), 2-trimethylsilyl-ethanesulfonyl(“TES”), trityl and substituted trityl groups, allyloxycarbonyl,9-fluorenylmethyloxycarbonyl (“FMOC”), nitro-veratryloxycarbonyl(“NVOC”) and the like. Representative hydroxyl protecting groupsinclude, but are not limited to, those where the hydroxyl group iseither acylated (esterified) or alkylated such as benzyl and tritylethers, as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilylethers (e.g., TMS or TIPS groups), glycol ethers, such as ethyleneglycol and propylene glycol derivatives and allyl ethers.

II. Description of the Invention

This invention is based on the discovery that enantioenrichedα-quaternary Mannich adducts of α-alkyl-substituted ketones could beaccessed via aminomethylation followed by allylic alkylation (Scheme 1).Introduction of an aminomethyl group to β-keto ester V using classicalMannich chemistry (V to VI), followed by an asymmetric allylicalkylation reaction would provide the enantioenriched α-quaternaryketone product VII. Compound VII can be thought of as anα-aminomethylation product of the so-called “thermodynamic” enolate.

The use of β-oxo esters circumvents any undesired regioselectivity inthe aminomethylation step. Next, a palladium-catalyzed decarboxylationevent furnishes the desired enolate intermediate under conditionsamenable to enantioinduction. As demonstrated herein, these reactionsproceed in high yield and enantioselectivity. The decarboxylativeallylic alkylation reaction is catalyzed by a transition metal catalystand a chiral ligand, and the products can be quickly and efficientlyelaborated into complex products exhibiting biological activity.

According to embodiments of the present invention, a wide range ofstructurally-diverse, functionalized α-quaternary Mannich-type productsare prepared in a two-step sequence by (i) Mannich reaction followed by(ii) a stereoselective method of palladium-catalyzed enantioselectiveenolate allylic alkylation. In effect, the methods enable access toasymmetric Mannich-type products of “thermodynamic” enolates ofsubstrates possessing additional enolizable positions and acidicprotons. Palladium-catalyzed decarboxylative allylic alkylation enablesthe enantioselective synthesis of five-, six-, and seven-memberedketone, lactam, and other heterocyclic systems. The mild reactionconditions are notable given the free N—H groups and high functionalgroup tolerance in each of the substrates. Indeed, the utility of thismethod is highlighted in the first total synthesis of (+)-sibirinine.

In some embodiments of the present invention, a method of making anα-quaternary Mannich-type product comprises reacting a substratecompound with a ligand in the presence of a palladium-based catalyst anda solvent. The palladium-based catalysts, ligands and solvents useful inthis reaction are described in more detail below in Section IV.

III. Compounds of the Invention

In certain embodiments, the invention relates to a compound of formula(I),

or a salt thereof;wherein:

-   R^(1a) and R^(1b) each independently represent hydrogen or    optionally substituted alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl,    aralkyl, heteroaryl, heteroaralkyl, alkenyl, alkynyl, —C(O)alkyl,    —C(O)aryl, —C(O)aralkyl, —C(O)heteroaryl, —C(O)heteroaralkyl,    —C(O)O(alkyl), —C(O)O(aryl), —C(O)O(aralkyl), —C(O)O(heteroaryl),    —C(O)O(heteroaralkyl), —S(O)₂(aryl), —S(O)₂(alkyl),    —S(O)₂(haloalkyl), —OR¹⁴, —SR¹⁴, or —NR¹⁴R¹⁵;-   R² and R³ each independently represent hydrogen or substituted or    unsubstituted alkyl, aralkyl, aryl, heteroaralkyl, heteroaryl,    (cycloalkyl)alkyl, cycloalkyl, (heterocycloalkyl)alkyl,    heterocycloalkyl, alkenyl, alkynyl, alkylamino, hydroxyalkyl,    alkoxyalkyl, aminoalkyl, or thioalkyl;-   or wherein R^(1a) and R² are taken together with the intervening    atoms to form an optionally substituted heterocyclic ring;-   R⁸, R⁹, R¹⁰, and R¹¹ are independently selected for each occurrence    from hydrogen, hydroxyl, halogen, nitro, alkyl, alkenyl, alkynyl,    cyano, carboxyl, sulfate, amino, alkoxy, alkylamino, alkylthio,    hydroxyalkyl, alkoxyalkyl, aminoalkyl, thioalkyl, ether, thioether,    ester, amide, thioester, carbonate, carbamate, urea, sulfonate,    sulfone, sulfoxide, sulfonamide, acyl, acyloxy, acylamino, aryl,    heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl, arylalkoxy,    heteroaralkyl, (cycloalkyl)alkyl, and (heterocycloalkyl)alkyl;-   W¹ and W² are each independently selected from alkyl, alkenyl,    alkynyl, OR¹², SR¹², or NR¹²R¹³; or W¹ and W², taken together with    the intervening atoms, form an optionally substituted    heterocycloalkyl, cycloalkyl, heterocycloalkenyl, or cycloalkenyl    group;-   R¹² and R¹³ are independently selected for each occurrence from    hydrogen or substituted or unsubstituted alkyl, aralkyl, aryl,    heteroaralkyl, heteroaryl, (cycloalkyl)alkyl, cycloalkyl,    (heterocycloalkyl)alkyl, heterocycloalkyl, alkenyl, alkynyl,    hydroxyalkyl, alkoxyalkyl, aminoalkyl, and thioalkyl; and-   R¹⁴ and R¹⁵ are independently selected for each occurrence from    hydrogen or substituted or unsubstituted alkyl, aralkyl, aryl,    heteroaralkyl, heteroaryl, (cycloalkyl)alkyl, cycloalkyl,    (heterocycloalkyl)alkyl, heterocycloalkyl, alkenyl, and alkynyl.

In certain embodiments, W¹ and W², taken together with the interveningatoms, form an optionally substituted heterocycloalkyl, cycloalkyl,heterocycloalkenyl, or cycloalkenyl group.

In certain embodiments, the compound of formula (I) is represented byformula (Ia),

wherein:

-   A, B, C, and D each independently represent, as valence permits,    NR′, CR″R′″, C(O), O, S, CR″, or N; provided that no two adjacent    occurrences of A, B, C, and D are NR′, O, S, or N;-   R′ represents hydrogen or optionally substituted alkyl, cycloalkyl,    (cycloalkyl)alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,    alkenyl, alkynyl, —C(O)alkyl, —C(O)aryl, —C(O)aralkyl,    —C(O)heteroaryl, —C(O)heteroaralkyl, —C(O)O(alkyl), —C(O)O(aryl),    —C(O)O(aralkyl), —C(O)O(heteroaryl), —C(O)O(heteroaralkyl),    —S(O)₂(aryl), —S(O)₂(alkyl), —S(O)₂(haloalkyl), —OR¹⁴, —SR¹⁴, or    —NR¹⁴R¹⁵;-   R″ and R′″ each independently represent hydrogen, hydroxyl, halogen,    nitro, alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl,    heteroaryl, heteroaralkyl, (heterocycloalkyl)alkyl,    heterocycloalkyl, alkenyl, alkynyl, cyano, carboxyl, sulfate, amino,    alkoxy, aryloxy, alkylamino, alkylthio, hydroxyalkyl, alkoxyalkyl,    aminoalkyl, thioalkyl, ether, thioether, ester, amide, thioester,    carbonate, carbamate, urea, sulfonate, sulfone, sulfoxide,    sulfonamide, acyl, acyloxy, or acylamino;-   or any two occurrences of R′, R″, and R′″ on adjacent A, B, C, or D    groups, taken together with the intervening atoms, form an    optionally substituted aryl, heteroaryl, cycloalkyl, cycloalkenyl,    heterocycloalkyl, or heterocycloalkenyl group;-   each occurrence of    independently represents a double bond or a single bond as permitted    by valence; and-   m and n are integers each independently selected from 0, 1, and 2.

In certain embodiments, the sum of m and n is 0, 1, 2, or 3.

In certain embodiments, each occurrence of A, B, C, and D is eachindependently CR″R′″ or CR″.

In certain embodiments, each occurrence of A, B, C, and D is CR″R′″.

In certain such embodiments, R″ and R′″ are each independently selectedfor each occurrence from hydrogen, hydroxyl, halogen, alkyl, cycloalkyl,(cycloalkyl)alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,(heterocycloalkyl)alkyl, heterocycloalkyl, alkenyl, alkynyl, amino,alkoxy, aryloxy, and alkylamino.

In certain preferred embodiments, each occurrence of A, B, C, and D isCH₂.

In certain embodiments, at least two adjacent occurrences of A, B, C,and D are CR″. In accordance with valence requirements, there exists adouble bond between the two adjacent occurrences of CR″.

In certain embodiments, A and B are each CR″ and m is 1. In suchembodiments, there exists a double bond between A and B.

In certain such embodiments, R″ is independently selected for eachoccurrence from hydrogen, hydroxyl, halogen, alkyl, cycloalkyl,(cycloalkyl)alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,(heterocycloalkyl)alkyl, heterocycloalkyl, alkenyl, alkynyl, amino,alkoxy, aryloxy, and alkylamino.

In alternative embodiments, the occurrence of R″ on A and the occurrenceof R″ on B are taken together to form an optionally substituted aryl,heteroaryl, cycloalkenyl, or heterocycloalkenyl group. In certainpreferred embodiments, the occurrence of R″ on A and the occurrence ofR″ on B are taken together to form an optionally substituted aryl orheteroaryl group.

In certain embodiments, at least one occurrence of A, B, C, and D isNR′.

In certain such embodiments, at least one occurrence of the remaining A,B, C, and D is NR′ or O.

In certain such embodiments, R′ represents independently for eachoccurrence hydrogen or optionally substituted alkyl, aralkyl,heteroaralkyl, —C(O)alkyl, —C(O)aryl, —C(O)aralkyl, —C(O)O(alkyl),—C(O)O(aryl), —C(O)O(aralkyl), or —S(O)₂(aryl).

For embodiments of the compound of formula (Ia) having two or more A, B,C, or D groups, no two adjacent A groups, B groups, C groups, or Dgroups are NR′, O, S, or N.

In certain embodiments, R⁸, R⁹, R¹⁰, and R¹¹ are each independentlyselected for each occurrence from hydrogen, halogen, cyano, alkyl,alkoxy, alkylthio, aryl, aralkyl, alkenyl, alkynyl, heteroaryl, andheteroaralkyl.

In certain embodiments, R⁸, R⁹, R¹⁰, and R¹¹ are each independentlyselected for each occurrence from hydrogen, alkyl, aryl, aralkyl,alkenyl, alkynyl, heteroaryl, and heteroaralkyl.

In certain embodiments, R⁸, R⁹, R¹⁰, and R¹¹ are each hydrogen.

In certain embodiments, R² and R³ are each independently selected fromhydrogen and alkyl.

In certain embodiments, R² and R³ are each hydrogen.

In certain embodiments, R^(1a) represents hydrogen or optionallysubstituted alkyl, aralkyl, heteroaralkyl, —C(O)alkyl, —C(O)aryl,—C(O)aralkyl, —C(O)O(alkyl), —C(O)O(aryl), —C(O)O(aralkyl), or—S(O)₂(aryl). In certain such embodiments, R^(1b) is H.

In certain preferred embodiments, R^(1a) represents hydrogen oroptionally substituted alkyl, —C(O)alkyl, —C(O)aryl, —C(O)aralkyl,—C(O)O(alkyl), —C(O)O(aryl), —C(O)O(aralkyl), or —S(O)₂(aryl). Incertain such embodiments, R^(1b) is H.

In some embodiments, R^(1a) and R^(1b) both are H.

In certain preferred embodiments, the compound of formula (I) or (Ia) isenantioenriched.

In certain embodiments, the compound of formula (I) or (Ia) has morethan one stereogenic center. An exemplary compound having more than onestereogenic center may occur when R^(1a) and R² are taken together withthe intervening atoms to form an optionally substituted heterocyclicring. In certain such embodiments, the compound of formula (I) or (Ia)is enantioenriched, diasteroenriched, or both.

In certain embodiments, the invention relates to a compound of formula(II),

or a salt thereof;wherein:

-   R^(1a) and R^(1b) each independently represent hydrogen or    optionally substituted alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl,    aralkyl, heteroaryl, heteroaralkyl, alkenyl, alkynyl, —C(O)alkyl,    —C(O)aryl, —C(O)aralkyl, —C(O)heteroaryl, —C(O)heteroaralkyl,    —C(O)O(alkyl), —C(O)O(aryl), —C(O)O(aralkyl), —C(O)O(heteroaryl),    —C(O)O(heteroaralkyl), —S(O)₂(aryl), —S(O)₂(alkyl),    —S(O)₂(haloalkyl), —OR¹⁴, —SR¹⁴, or —NR¹⁴R¹⁵;-   R² and R³ each independently represent hydrogen or substituted or    unsubstituted alkyl, aralkyl, aryl, heteroaralkyl, heteroaryl,    (cycloalkyl)alkyl, cycloalkyl, (heterocycloalkyl)alkyl,    heterocycloalkyl, alkenyl, alkynyl, alkylamino, hydroxyalkyl,    alkoxyalkyl, aminoalkyl, or thioalkyl;-   or wherein R^(1a) and R² are taken together with the intervening    atoms to form an optionally substituted heterocyclic ring;-   R⁴, R⁵, R⁶, and R⁷ are independently selected for each occurrence    from hydrogen, hydroxyl, halogen, nitro, alkyl, alkenyl, alkynyl,    cyano, carboxyl, sulfate, amino, alkoxy, alkylamino, alkylthio,    hydroxyalkyl, alkoxyalkyl, aminoalkyl, thioalkyl, ether, thioether,    ester, amide, thioester, carbonate, carbamate, urea, sulfonate,    sulfone, sulfoxide, sulfonamide, acyl, acyloxy, acylamino, aryl,    heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl, arylalkoxy,    heteroaralkyl, (cycloalkyl)alkyl, and (heterocycloalkyl)alkyl;-   W¹ and W² are each independently selected from alkyl, alkenyl,    alkynyl, OR¹², SR¹², or NR¹²R¹³; or W¹ and W², taken together with    the intervening atoms, form an optionally substituted    heterocycloalkyl, cycloalkyl, heterocycloalkenyl, or cycloalkenyl    group;-   R¹² and R¹³ are independently selected for each occurrence from    hydrogen or substituted or unsubstituted alkyl, aralkyl, aryl,    heteroaralkyl, heteroaryl, (cycloalkyl)alkyl, cycloalkyl,    (heterocycloalkyl)alkyl, heterocycloalkyl, alkenyl, alkynyl,    hydroxyalkyl, alkoxyalkyl, aminoalkyl, and thioalkyl; and-   R¹⁴ and R¹⁵ are independently selected for each occurrence from    hydrogen or substituted or unsubstituted alkyl, aralkyl, aryl,    heteroaralkyl, heteroaryl, (cycloalkyl)alkyl, cycloalkyl,    (heterocycloalkyl)alkyl, heterocycloalkyl, alkenyl, and alkynyl.

In certain embodiments, the compound of formula (II) is represented byformula (IIa),

wherein:

-   A, B, C, and D each independently represent, as valence permits,    NR′, CR″R′″, C(O), O, S, CR″, or N; provided that no two adjacent    occurrences of A, B, C, and D are NR′, O, S, or N;-   R′ represents hydrogen or optionally substituted alkyl, cycloalkyl,    (cycloalkyl)alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,    alkenyl, alkynyl, —C(O)alkyl, —C(O)aryl, —C(O)aralkyl,    —C(O)heteroaryl, —C(O)heteroaralkyl, —C(O)O(alkyl), —C(O)O(aryl),    —C(O)O(aralkyl), —C(O)O(heteroaryl), —C(O)O(heteroaralkyl),    —S(O)₂(aryl), —S(O)₂(alkyl), —S(O)₂(haloalkyl), —OR¹⁴, —SR¹⁴, or    —NR¹⁴R¹⁵;-   R″ and R′″ each independently represent hydrogen, hydroxyl, halogen,    nitro, alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl,    heteroaryl, heteroaralkyl, (heterocycloalkyl)alkyl,    heterocycloalkyl, alkenyl, alkynyl, cyano, carboxyl, sulfate, amino,    alkoxy, aryloxy, alkylamino, alkylthio, hydroxyalkyl, alkoxyalkyl,    aminoalkyl, thioalkyl, ether, thioether, ester, amide, thioester,    carbonate, carbamate, urea, sulfonate, sulfone, sulfoxide,    sulfonamide, acyl, acyloxy, or acylamino;-   or any two occurrences of R′, R″, and R′″ on adjacent A, B, C, or D    groups, taken together with the intervening atoms, form an    optionally substituted aryl, heteroaryl, cycloalkyl, cycloalkenyl,    heterocycloalkyl, or heterocycloalkenyl group;-   each occurrence of    independently represents a double bond or a single bond as permitted    by valence; and-   m and n are integers each independently selected from 0, 1, and 2.

In certain embodiments, the sum of m and n is 0, 1, 2, or 3.

In certain embodiments, each occurrence of A, B, C, and D is eachindependently CR″R′″ or CR″.

In certain embodiments, each occurrence of A, B, C, and D is CR″R′″.

In certain such embodiments, R″ and R′″ are each independently selectedfor each occurrence from hydrogen, hydroxyl, halogen, alkyl, cycloalkyl,(cycloalkyl)alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,(heterocycloalkyl)alkyl, heterocycloalkyl, alkenyl, alkynyl, amino,alkoxy, aryloxy, and alkylamino.

In certain preferred embodiments, each occurrence of A, B, C, and D isCH₂.

In certain embodiments, at least two adjacent occurrences of A, B, C,and D are CR″. In accordance with valence requirements, there exists adouble bond between the two adjacent occurrences of CR″.

In certain embodiments, A and B are each CR″ and m is 1. In suchembodiments, there exists a double bond between A and B.

In certain such embodiments, R″ is independently selected for eachoccurrence from hydrogen, hydroxyl, halogen, alkyl, cycloalkyl,(cycloalkyl)alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,(heterocycloalkyl)alkyl, heterocycloalkyl, alkenyl, alkynyl, amino,alkoxy, aryloxy, and alkylamino.

In alternative embodiments, the occurrence of R″ on A and the occurrenceof R″ on B are taken together to form an optionally substituted aryl,heteroaryl, cycloalkenyl, or heterocycloalkenyl group. In certainpreferred embodiments, the occurrence of R″ on A and the occurrence ofR″ on B are taken together to form an optionally substituted aryl orheteroaryl group.

In certain embodiments, at least one occurrence of A, B, C, and D isNR′.

In certain such embodiments, at least one occurrence of the remaining A,B, C, and D is NR′ or O.

In certain such embodiments, R′ represents independently for eachoccurrence hydrogen or optionally substituted alkyl, aralkyl,heteroaralkyl, —C(O)alkyl, —C(O)aryl, —C(O)aralkyl, —C(O)O(alkyl),—C(O)O(aryl), —C(O)O(aralkyl), or —S(O)₂(aryl).

For embodiments of the compound of formula (IIa) having two or more A,B, C, or D groups, no two adjacent A groups, B groups, C groups, or Dgroups are NR′, O, S, or N.

In certain embodiments, R⁴, R⁵, R⁶, and R⁷ are each independentlyselected for each occurrence from hydrogen, halogen, cyano, alkyl,alkoxy, alkylthio, aryl, aralkyl, alkenyl, alkynyl, heteroaryl, andheteroaralkyl.

In certain embodiments, R⁴, R⁵, R⁶, and R⁷ are each independentlyselected for each occurrence from hydrogen, alkyl, aryl, aralkyl,alkenyl, alkynyl, heteroaryl, and heteroaralkyl.

In certain embodiments, R⁴, R⁵, R⁶, and R⁷ are each hydrogen.

In certain embodiments, R² and R³ are each independently selected fromhydrogen and alkyl.

In certain embodiments, R² and R³ are each hydrogen.

In certain embodiments, R^(1a) represents hydrogen or optionallysubstituted alkyl, aralkyl, heteroaralkyl, —C(O)alkyl, —C(O)aryl,—C(O)aralkyl, —C(O)O(alkyl), —C(O)O(aryl), —C(O)O(aralkyl), or—S(O)₂(aryl). In certain such embodiments, R^(1b) is H.

In certain preferred embodiments, R^(1a) represents hydrogen oroptionally substituted alkyl, —C(O)alkyl, —C(O)aryl, —C(O)aralkyl,—C(O)O(alkyl), —C(O)O(aryl), —C(O)O(aralkyl), or —S(O)₂(aryl). Incertain such embodiments, R^(1b) is H.

In some embodiments, R^(1a) and R^(1b) both are H.

IV. Methods of the Invention

In certain embodiments, the invention provides methods for thepreparation of a compound of formula (I):

comprising treating a compound of formula (II):

with a transition metal catalyst under alkylation conditions, wherein,as valence and stability permit,

-   R^(1a) and R^(1b) each independently represent hydrogen or    optionally substituted alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl,    aralkyl, heteroaryl, heteroaralkyl, alkenyl, alkynyl, —C(O)alkyl,    —C(O)aryl, —C(O)aralkyl, —C(O)heteroaryl, —C(O)heteroaralkyl,    —C(O)O(alkyl), —C(O)O(aryl), —C(O)O(aralkyl), —C(O)O(heteroaryl),    —C(O)O(heteroaralkyl), —S(O)₂(aryl), —S(O)₂(alkyl),    —S(O)₂(haloalkyl), —OR¹⁴, —SR¹⁴, or —NR¹⁴R¹⁵;-   R² and R³ each independently represent hydrogen or substituted or    unsubstituted alkyl, aralkyl, aryl, heteroaralkyl, heteroaryl,    (cycloalkyl)alkyl, cycloalkyl, (heterocycloalkyl)alkyl,    heterocycloalkyl, alkenyl, alkynyl, alkylamino, hydroxyalkyl,    alkoxyalkyl, aminoalkyl, or thioalkyl;-   or wherein R^(1a) and R² are taken together with the intervening    atoms to form an optionally substituted heterocyclic ring;-   R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, and R¹¹ are each independently selected    for each occurrence from hydrogen, hydroxyl, halogen, nitro, alkyl,    alkenyl, alkynyl, cyano, carboxyl, sulfate, amino, alkoxy,    alkylamino, alkylthio, hydroxyalkyl, alkoxyalkyl, aminoalkyl,    thioalkyl, ether, thioether, ester, amide, thioester, carbonate,    carbamate, urea, sulfonate, sulfone, sulfoxide, sulfonamide, acyl,    acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocycloalkyl,    aralkyl, arylalkoxy, heteroaralkyl, (cycloalkyl)alkyl, and    (heterocycloalkyl)alkyl;-   W¹ and W² are each independently selected from alkyl, alkenyl,    alkynyl, OR¹², SR¹², or NR¹²R¹³; or W¹ and W², taken together with    the intervening atoms, form an optionally substituted    heterocycloalkyl, cycloalkyl, heterocycloalkenyl, or cycloalkenyl    group;-   R¹² and R¹³ are independently selected for each occurrence from    hydrogen or substituted or unsubstituted alkyl, aralkyl, aryl,    heteroaralkyl, heteroaryl, (cycloalkyl)alkyl, cycloalkyl,    (heterocycloalkyl)alkyl, heterocycloalkyl, alkenyl, alkynyl,    hydroxyalkyl, alkoxyalkyl, aminoalkyl, and thioalkyl; and-   R¹⁴ and R¹⁵ are independently selected for each occurrence from    hydrogen or substituted or unsubstituted alkyl, aralkyl, aryl,    heteroaralkyl, heteroaryl, (cycloalkyl)alkyl, cycloalkyl,    (heterocycloalkyl)alkyl, heterocycloalkyl, alkenyl, and alkynyl.

In certain embodiments, W¹ and W², taken together with the interveningatoms, form an optionally substituted heterocycloalkyl, cycloalkyl,heterocycloalkenyl, or cycloalkenyl group.

In certain embodiments, formula (I) is represented by formula (Ia),

and formula (II) is represented by formula (IIa),

wherein:

-   A, B, C, and D each independently represent, as valence permits,    NR′, CR″R′″, C(O), O, S, CR″, or N; provided that no two adjacent    occurrences of A, B, C, and D are NR′, O, S, or N;-   R′ represents hydrogen or optionally substituted alkyl, cycloalkyl,    (cycloalkyl)alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,    alkenyl, alkynyl, —C(O)alkyl, —C(O)aryl, —C(O)aralkyl,    —C(O)heteroaryl, —C(O)heteroaralkyl, —C(O)O(alkyl), —C(O)O(aryl),    —C(O)O(aralkyl), —C(O)O(heteroaryl), —C(O)O(heteroaralkyl),    —S(O)₂(aryl), —S(O)₂(alkyl), —S(O)₂(haloalkyl), —OR¹⁴, —SR¹⁴, or    —NR¹⁴R¹⁵;-   R″ and R′″ each independently represent hydrogen, hydroxyl, halogen,    nitro, alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl,    heteroaryl, heteroaralkyl, (heterocycloalkyl)alkyl,    heterocycloalkyl, alkenyl, alkynyl, cyano, carboxyl, sulfate, amino,    alkoxy, aryloxy, alkylamino, alkylthio, hydroxyalkyl, alkoxyalkyl,    aminoalkyl, thioalkyl, ether, thioether, ester, amide, thioester,    carbonate, carbamate, urea, sulfonate, sulfone, sulfoxide,    sulfonamide, acyl, acyloxy, or acylamino;-   or any two occurrences of R′, R″, and R′″ on adjacent A, B, C, or D    groups, taken together with the intervening atoms, form an    optionally substituted aryl, heteroaryl, cycloalkyl, cycloalkenyl,    heterocycloalkyl, or heterocycloalkenyl group;-   each occurrence of    independently represents a double bond or a single bond as permitted    by valence; and-   m and n are integers each independently selected from 0, 1, and 2.

In certain embodiments, the sum of m and n is 0, 1, 2, or 3.

In certain embodiments, each occurrence of A, B, C, and D is eachindependently CR″R′″ or CR″.

In certain embodiments, each occurrence of A, B, C, and D is CR″R′″.

In certain such embodiments, R″ and R′″ are each independently selectedfor each occurrence from hydrogen, hydroxyl, halogen, alkyl, cycloalkyl,(cycloalkyl)alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,(heterocycloalkyl)alkyl, heterocycloalkyl, alkenyl, alkynyl, amino,alkoxy, aryloxy, and alkylamino.

In certain preferred embodiments, each occurrence of A, B, C, and D isCH₂.

In certain embodiments, at least two adjacent occurrences of A, B, C,and D are CR″.

In certain embodiments, A and B are each CR″ and m is 1.

In certain such embodiments, R″ is independently selected for eachoccurrence from hydrogen, hydroxyl, halogen, alkyl, cycloalkyl,(cycloalkyl)alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,(heterocycloalkyl)alkyl, heterocycloalkyl, alkenyl, alkynyl, amino,alkoxy, aryloxy, and alkylamino.

In alternative embodiments, the occurrence of R″ on A and the occurrenceof R″ on B are taken together to form an optionally substituted aryl,heteroaryl, cycloalkenyl, or heterocycloalkenyl group.

In certain embodiments, at least one occurrence of A, B, C, and D isNR′.

In certain such embodiments, at least one occurrence of the remaining A,B, C, and D is NR′ or O.

In certain such embodiments, R′ represents independently for eachoccurrence hydrogen or optionally substituted alkyl, aralkyl,heteroaralkyl, —C(O)alkyl, —C(O)aryl, —C(O)aralkyl, —C(O)O(alkyl),—C(O)O(aryl), —C(O)O(aralkyl), or —S(O)₂(aryl).

For embodiments of the compound of formula (Ia) or (IIa) having two ormore A, B, C, or D groups, no two adjacent A groups, B groups, C groups,or D groups are NR′, O, S, or N.

In certain embodiments, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, and R¹¹ are eachindependently selected for each occurrence from hydrogen, halogen,cyano, alkyl, alkoxy, alkylthio, aryl, aralkyl, alkenyl, alkynyl,heteroaryl, and heteroaralkyl.

In certain embodiments, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, and R¹¹ are eachindependently selected for each occurrence from hydrogen, alkyl, aryl,aralkyl, alkenyl, alkynyl, heteroaryl, and heteroaralkyl.

In certain embodiments, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, and R¹¹ are eachhydrogen.

In certain embodiments, R² and R³ are each independently selected fromhydrogen and alkyl.

In certain embodiments, R² and R³ are each hydrogen.

In certain embodiments, R^(1a) represents hydrogen or optionallysubstituted alkyl, aralkyl, heteroaralkyl, —C(O)alkyl, —C(O)aryl,—C(O)aralkyl, —C(O)O(alkyl), —C(O)O(aryl), —C(O)O(aralkyl), or—S(O)₂(aryl). In certain such embodiments, R^(1b) is H.

In certain preferred embodiments, R^(1a) represents hydrogen oroptionally substituted alkyl, —C(O)alkyl, —C(O)aryl, —C(O)aralkyl,—C(O)O(alkyl), —C(O)O(aryl), —C(O)O(aralkyl), or —S(O)₂(aryl). Incertain such embodiments, R^(1b) is H.

In some embodiments, R^(1a) and R^(1b) both are H.

In certain preferred embodiments of the methods described herein, thecompound of formula (I) generated by the methods is enantioenriched.

In certain embodiments of the methods, the compound of formula (I)generated by the methods of the invention has more than one stereogeniccenter. In certain such embodiments, the compound of formula (I) isenantioenriched, diastereoenriched, or both.

In certain embodiments, the method further comprises contacting acompound of formula (III):

with an imine of formula (IV):

under conditions sufficient to produce a compound of formula (II).

In certain embodiments, the step of contacting a compound of formula(III) with an imine of formula (IV) occurs under basic conditions.

In certain embodiments, the imine of formula (IV) is generated in situ.For example, the starting material can be a sulfonylmethyl carbamate,which eliminates a hydrogen sulfone under basic conditions, generatingthe imine in situ. Without being bound to theory, this basic environmentcan also promote the subsequent Mannich reaction.

In certain embodiments, the method of preparing a compound of formula(I) from the compound of formula (III) occurs in a two-step, two-potsynthetic procedure.

Alternatively, the method of preparing a compound of formula (I) fromthe compound of formula (III) occurs in a one-pot synthetic procedurethat begins with (i) a Mannich reaction followed by (ii) adecarboxylative allylic alkylation reaction.

Transition Metal Catalysts

Preferred transition metal catalysts of the invention are complexes oftransition metals wherein the metal is selected from Groups 6, 8, 9 and10 in the periodic table. In preferred embodiments, the metal of thetransition metal catalyst is selected from molybdenum, tungsten,iridium, rhenium, ruthenium, nickel, platinum, and palladium. In morepreferred embodiments, the transition metal catalyst comprises atransition metal selected from palladium, nickel, and platinum, mostpreferably palladium.

In certain embodiments of the invention, the transition metal complexutilized in the reaction includes a transition metal that has a lowoxidation state, typically (0) or (I). A low oxidation state enables themetal to undergo oxidative addition to the substrate. It should beappreciated that the air- and moisture-sensitivity of many suchcomplexes of transition metals will necessitate appropriate handlingprecautions. This may include the following precautions withoutlimitation: minimizing exposure of the reactants to air and water priorto reaction; maintaining an inert atmosphere within the reaction vessel;properly purifying all reagents; and removing water from reactionvessels prior to use.

Exemplary transition metal catalysts include, without limitation,Mo(CO)₆, Mo(MeCN)₃(CO)₃, W(CO)₆, W(MeCN)₃(CO)₃,[Ir(1,5-cyclooctadiene)Cl]₂, [IR(1,5-cyclooctadiene)Cl]₂,[Ir(1,5-cyclooctadiene)Cl]₂, Rh(PPh₃)₃Cl, [Rh(1,5-cyclooctadiene)Cl]₂,Ru(pentamethylcyclopentadienyl)(MeCN)₃PF₆, Ni(1,5-cyclooctadiene)₂,Ni[P(OEt)₃]₄, tris(dibenzylideneacetone)dipalladium(0),tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct,tris(bis(4-methoxybenzylidene)acetone)dipalladium(0), Pd(OC(═O)CH₃)₂[Pd(OAc)₂], Pd(3,5-dimethyloxy-dibenzylideneacetone)₂, PdCl₂(R²³CN)₂;PdCl₂(PR²⁴R²⁵R²⁶)₂; [Pd(η³-allyl)Cl]₂; and Pd(PR²⁴R²⁵R²⁶)₄, wherein R²³,R²⁴, R²⁵, and R²⁶ are independently selected from hydrocarbyl,substituted hydrocarbyl, heteroatom-containing hydrocarbyl, andsubstituted heteroatom-containing hydrocarbyl. In particularembodiments, the transition metal catalysttris(dibenzylideneacetone)dipalladium, Pd₂(dba)₃, ortris(bis(4-methoxybenzylidene)acetone) dipalladium, Pd₂(pmdba)₃, ispreferred.

To improve the effectiveness of the catalysts discussed herein,additional reagents may be employed as needed, including, withoutlimitation, salts, solvents, and other small molecules. Preferredadditives include AgBF₄, AgOSO₂CF₃, AgOC(═O)CH₃, and bipyridine. Theseadditives are preferably used in an amount that is in the range of about1 equivalent to about 5 equivalents relative to the amount of thecatalyst.

A low oxidation state of a transition metal, i.e., an oxidation statesufficiently low to undergo oxidative addition, can also be obtained insitu, by the reduction of transition metal complexes that have a highoxidation state. Reduction of the transition metal complex can beachieved by adding nucleophilic reagents including, without limitation,NBu₄OH, tetrabutylammonium difluorotriphenylsilicate (TBAT),tetrabutylammonium fluoride (TBAF), 4-dimethylaminopyridine (DMAP),NMe₄OH(H₂O)₅, KOH/1,4,7,10,13,16-hexaoxacyclooctadecane, EtONa,TBAT/trimethyl-(2-methyl-cyclohex-1-enyloxy)-silane, and mixturesthereof. When a nucleophilic reagent is needed for the reduction of themetal complex, the nucleophilic reagent is used in an amount in therange of about 1 mol % to about 20 mol % relative to the reactant, morepreferably in the range of about 1 mol % to about 10 mol % relative tothe substrate, and most preferably in the range of about 5 mol % toabout 8 mol % relative to the substrate.

In certain embodiments, a Pd(II) complex can be reduced in situ to forma Pd(0) catalyst. Exemplary transition metal complexes that may bereduced in situ, include, without limitation,allylchloro[1,3-bis(2,6-di-i-propylphenyl)imidazol-2-ylidene]palladium(II),([2S,3S]-bis[diphenylphosphino]butane)(η³-allyl)palladium(II)perchlorate,[S]-4-tert-butyl-2-(2-diphenylphosphanyl-phenyl)-4,5-dihydro-oxazole(η³-allyl)palladium(II)hexafluorophosphate (i.e., [Pd(S-tBu-PHOX)(allyl)]PF₆), andcyclopentadienyl(η³-allyl) palladium(II), with[Pd(s-tBu-PHOX)(allyl)]PF₆ and cyclopentadienyl(η³-allyl)palladium(II)being most preferred.

In certain embodiments, the transition metal is palladium. In certainembodiments, the transition metal catalyst is a dimer of a transitionmetal. Exemplary dimeric transition metal catalysts include Pd₂(dba)₃and Pd₂(pmdba)₃. In certain preferred embodiments, the transition metalcatalyst is Pd₂(dba)₃ or Pd₂(pmdba)₃. In embodiments of the methodwherein the transition metal catalyst is a dimer, the amount of totaltransition metal present in the reaction is twice the amount of thetransition metal catalytic complex.

Accordingly, when describing the amount of transition metal catalystused in the methods of the invention, the following terminology applies.The amount of transition metal catalyst present in a reaction isalternatively referred to herein as “catalyst loading”. Catalyst loadingmay be expressed as a percentage that is calculated by dividing themoles of catalyst complex by the moles of the substrate present in agiven reaction. Catalyst loading is alternatively expressed as apercentage that is calculated by dividing the moles of total transitionmetal (for example, palladium) by the moles of the substrate present ina given reaction. For example, in a reaction that uses 5 mol % dimericcatalyst (e.g, Pd₂(dba)₃), this amount of transition metal catalyst canbe alternatively expressed as 10 mol % total transition metal (e.g.,Pd(0)).

In certain embodiments, the transition metal catalyst is present underthe conditions of the reaction from an amount of about 0.1 mol % toabout 20 mol % total palladium relative to the substrate, which is thecompound of formula (II) or (IIa). In certain embodiments, the catalystloading is from about 1 mol % to about 15 mol % total palladium relativeto the substrate. For example, in certain embodiments, the catalystloading is about 1 mol %, about 2 mol %, about 3 mol %, about 5 mol %,about 6 mol %, about 8 mol %, about 9 mol %, about 10 mol %, about 11mol %, about 12 mol %, or about 15 mol % total palladium.

Ligands

One aspect of the invention relates to the enantioselectivity of themethods. Enantioselectivity results from the use of chiral ligandsduring the allylic alkylation reaction. Accordingly, in certainembodiments, the transition metal catalyst further comprises a chiralligand. Without being bound by theory, the asymmetric environment thatis created around the metal center by the presence of chiral ligandsproduces an enantioselective reaction. The chiral ligand forms a complexwith the transition metal, thereby occupying one or more of thecoordination sites on the metal and creating an asymmetric environmentaround the metal center. This complexation may or may not involve thedisplacement of achiral ligands already complexed to the metal. Whendisplacement of one or more achiral ligands occurs, the displacement mayproceed in a concerted fashion, i.e., with both the achiral liganddecomplexing from the metal and the chiral ligand complexing to themetal in a single step. Alternatively, the displacement may proceed in astepwise fashion, i.e., with decomplexing of the achiral ligand andcomplexing of the chiral ligand occurring in distinct steps.Complexation of the chiral ligand to the transition metal may be allowedto occur in situ, i.e., by admixing the ligand and metal before addingthe substrate. Alternatively, the ligand-metal complex can be formedseparately, and the complex isolated before use in the alkylationreactions of the present invention.

Once coordinated to the transition metal center, the chiral ligandinfluences the orientation of other molecules as they interact with thetransition metal catalyst. Coordination of the metal center with aπ-allyl group and reaction of the substrate with the π-allyl-metalcomplex are dictated by the presence of the chiral ligand. Theorientation of the reacting species determines the stereochemistry ofthe products.

Chiral ligands of the invention may be bidentate or monodentate or,alternatively, ligands with higher denticity (e.g., tridentate,tetradentate, etc.) can be used. Preferably, the ligand will besubstantially enantiopure. By “enantiopure” is meant that only a singleenantiomer is present. In many cases, substantially enantiopure ligandscan be purchased from commercial sources, obtained by successiverecrystallizations of an enantioenriched substance, or by other suitablemeans for separating enantiomers.

Exemplary chiral ligands may be found in U.S. Pat. No. 7,235,698, theentirely of which is incorporated herein by reference. In certainembodiments, the chiral ligand is an enantioenriched phosphine ligand.In certain embodiments, the enantioenriched phosphine ligand is aP,N-ligand such as a phosphinooxazoline (PHOX) ligand. Preferred chiralligands of the invention include the PHOX-type chiral ligands such as(R)-2-[2-(diphenylphosphino)phenyl]-4-isopropyl-2-oxazoline,(R)-2-[2-(diphenylphosphino)phenyl]-4-phenyl-2-oxazoline,(S)-2-[2-(diphenylphosphino)phenyl]-4-benzyl-2-oxazoline,(S)-2-[2-(diphenylphosphino)phenyl]-4-tert-butyl-2-oxazoline((S)-t-BuPHOX) and(S)-2-(2-(bis(4-(Trifluoromethyl)phenyl)phosphino)-5-(trifluoromethyl)phenyl)-4-(tert-butyl)-4,5-dihydrooxazole((S)-(CF₃)₃-t-BuPHOX). In preferred embodiments, the PHOX type chiralligand is selected from (S)-t-BuPHOX and (S)-(CF₃)₃-t-BuPHOX). Theligand structures are depicted below.

Generally, the chiral ligand is present in an amount in the range ofabout 0.75 equivalents to about 10 equivalents relative to the amount oftotal metal from the catalyst, preferably in the range of about 0.75 toabout 5 equivalents relative to the amount of total metal from thecatalyst, and most preferably in the range of about 0.75 to about 1.25,such as about 1.25 equivalents relative to the amount of total metalfrom the catalyst. Alternatively, the amount of the chiral ligand can bemeasured relative to the amount of the substrate.

In certain embodiments, the ligand is present under the conditions ofthe reaction from an amount of about 0.5 mol % to about 30 mol %relative to the substrate, which is the compound of formula (II) or(IIa). The amount of ligand present in the reaction is alternativelyreferred to herein as “ligand loading” and is expressed as a percentagethat is calculated by dividing the moles of ligand by the moles of thesubstrate present in a given reaction. In certain embodiments, theligand loading is from about 5 mol % to about 15 mol %. For example, incertain embodiments, the ligand loading is about about 5 mol %, about 6mol %, about 7.5 mol %, about 9 mol %, about 10 mol %, about 11 mol %,about 12 mol %, about 12.5 mol %, about 13 mol %, about 14 mol %, orabout 15 mol %. In certain embodiments, the ligand is in excess of thetransition metal catalyst. In certain embodiments, the ligand loading isabout 1.25 times the transition metal catalyst loading. In embodimentsin which the transition metal catalyst is a dimer, the ligand loading isabout 2.5 times the loading of the dimeric transition metal catalyst.

Where a chiral ligand is used, the reactions of the invention may enrichthe stereocenter α to the carbonyl (i.e., bearing C(R²)(R³)NH(R¹)) inthe product relative to the enrichment at this center, if any, of thestarting material. In certain embodiments, the chiral ligand used in themethods of the invention yields a compound of formula (I) or (Ia) thatis enantioenriched. The level of enantioenrichment of a compound may beexpressed as enantiomeric excess (ee). The ee of a compound may bemeasured by dividing the difference in the fractions of the enantiomersby the sum of the fractions of the enantiomers. For example, if acompound is found to comprise 98% (5)-enantiomer, and 2% (R) enantiomer,then the ee of the compound is (98−2)/(98+2), or 96%. In certainembodiments, the compound of formula (I) or (Ia) has about 30% ee orgreater, 40% ee or greater, 50% ee or greater, 60% ee or greater, 70% eeor greater, about 80% ee, about 85% ee, about 88% ee, about 90% ee,about 91% ee, about 92% ee, about 93% ee, about 94% ee, about 95% ee,about 96% ee, about 97% ee, about 98% ee, about 99% ee, or above about99% ee, even where this % ee is greater than the % ee of the startingmaterial, such as 0% ee (racemic). In certain embodiments, the compoundof formula (I) or (Ia) is enantioenriched. In certain embodiments, thecompound of formula (I) or (Ia) is enantiopure. In embodiments where thestarting material has more than one stereocenter, reactions of theinvention may enrich the stereocenter α to the carbonyl relative to theenrichment at this center, if any, of the starting material, andsubstantially independently of the stereochemical disposition/enrichmentof any other stereocenters of the molecule. For example, a product ofthe methods described herein may have 30% de or greater, 40% de orgreater, 50% de or greater, 60% de or greater, 70% de or greater, 80% deor greater, 90% de or greater, 95% de or greater, or even 98% de orgreater at the stereocenter α to the carbonyl.

In certain embodiments, the invention also relates to methods thatutilize an achiral ligand. Exemplary achiral ligands includetriphenylphosphine, tricyclohexylphosphine, tri-(ortho-tolyl)phosphine,trimethylphosphite, and triphenylphosphite.

Alkylation Conditions

In certain embodiments, the methods of the invention include treating acompound of formula (II) or (IIa) with a transition metal catalyst underalkylation conditions. In certain embodiments, alkylation conditions ofthe reaction include one or more organic solvents. In certainembodiments, organic solvents include aromatic or non-aromatichydrocarbons, ethers, alkylacetates, nitriles, or combinations thereof.In certain embodiments, organic solvents include hexane, pentane,benzene, toluene, xylene, cyclic ethers such as optionally substitutedtetrahydrofuran and dioxane, acyclic ethers such as dimethoxyethane,diethyl ether, methyl tertbutyl ether, and cyclopentyl methyl ether,acetonitrile, isobutyl acetate, ethyl acetate, isopropyl acetate, orcombinations thereof. In certain preferred embodiments, the solvent istoluene, methyl tertbutyl ether, cyclopentyl methyl ether,2-methyltetrahydrofuran, isobutyl acetate, ethyl acetate, or isopropylacetate. In certain other preferred embodiments, the solvent is toluene.

In certain embodiments, alkylation conditions of the reaction include areaction temperature. In certain embodiments, the reaction temperatureis ambient temperature (about 20° C. to about 26° C.). In certainembodiments, the reaction temperature is higher than ambienttemperature, such as, for example, about 30° C., about 35° C., about 40°C., about 45° C., about 50° C., about 55° C., or about 60° C. In certainembodiments, the reaction temperature is lower than ambient temperature,such as, for example, about 0° C.

EXEMPLIFICATION

The invention described generally herein will be more readily understoodby reference to the following examples, which are included merely forpurposes of illustration of certain aspects and embodiments of thepresent invention, and are not intended to limit the invention.

Example 1. Representative Synthesis for Preparation of α-Aminomethyl1,3-dicarbonyl Substrate

To introduce the aminomethyl moiety, sulfonylmethyl carbamates (e.g.,2a) were employed as versatile and readily available imine precursors.In the presence of Cs₂CO₃, the Boc-protected imine generated from 2reacted with β-keto ester 1 to smoothly afford β-aminoketone 3a,quantitatively, at ambient temperature. In a similar manner, otherprotected aminoketones 3b-g were obtained in good to excellent yields.

Representative Procedure A

Allyl1-(((tert-butoxycarbonyl)amino)methyl)-2-oxocyclohexane-1-carboxylate(3a). To a stirred solution of β-keto ester 1 (0.91 g, 5.0 mmol, 1equiv) in CH₂Cl₂ (25 mL) was added sulfonylmethyl carbamate 2a (1.63 g,6.0 mmol, 1.2 equiv) in one portion at ambient temperature. Afterstirring for 5 min, Cs₂CO₃ (4.70 g, 12.5 mmol, 2.5 equiv) was added inone portion. After 12 h, full consumption of starting material wasdetermined by TLC analysis. Saturated aqueous ammonium chloride wasadded slowly, and the biphasic mixture was stirred at ambienttemperature for 20 min and extracted with CH₂Cl₂ (3×25 mL). The combinedorganic layers were dried over Na₂SO₄, filtered, and concentrated invacuo. Flash column chromatography (SiO₂, 10% EtOAc in hexanes) affordedα-aminomethyl β-keto ester 3a (1.55 g, 99% yield) as a faintly yellowoil. R_(f)=0.55 (25% EtOAc in hexanes); ¹H NMR (500 MHz, CDCl₃) δ 5.91(ddt, J=16.5, 10.4, 5.8 Hz, 1H), 5.33 (m, 1H), 5.25 (m, 1H), 5.17 (m,1H), 4.63 (m, 2H), 3.54 (dd, J=13.9, 7.7 Hz, 1H), 3.40 (dd, J=13.9, 5.7Hz, 1H), 2.59-2.41 (m, 3H), 1.99 (m, 1H), 1.81 (m, 1H), 1.73-1.51 (m,3H), 1.40 (s, 9H); ¹³C NMR (126 MHz, CDCl₃) δ 209.0, 171.0, 156.0,131.6, 119.2, 79.4, 66.4, 62.4, 44.4, 40.9, 33.9, 28.5, 27.3, 22.2; IR(Neat Film, NaCl) 3461, 3404, 2976, 2939, 2867, 1713, 1501, 1452, 1366,1247, 1229, 1168, 1141 cm⁻¹; HRMS (FAB+) m/z calc'd for C₁₆H₂₆NO₅[M+H]⁺: 312.1811, found 312.1824.

Allyl 1-(benzyloxycarbonylaminomethyl)-2-oxocyclohexane-1-carboxylate(3b)

The reaction was conducted according to representative procedure A. Ketoester 1 (1.66 g, 9.09 mmol); sulfonylmethyl carbamate 2b (3.33 g, 10.9mmol); Cs₂CO₃ (7.40 g, 22.7 mmol). The reaction mixture was stirred for18 h. Flash column chromatography (SiO₂, 15% EtOAc in hexanes) affordedα-aminomethyl β-keto ester 3b (2.95 g, 8.54 mmol, 94% yield) as acolorless oil. R_(f)=0.27 (20% EtOAc in hexanes); ¹H NMR (500 MHz,CDCl₃) δ 7.38-7.28 (m, 5H), 5.86 (ddt, J=16.6, 10.5, 5.9 Hz, 1H), 5.41(m, 1H), 5.32 (m, 1H), 5.23 (m, 1H), 5.11-5.01 (m, 2H), 4.63-4.52 (m,2H), 3.62 (dd, J=13.8, 7.7 Hz, 1H), 3.46 (dd, J=13.8, 5.6 Hz, 1H),2.59-2.42 (m, 3H), 2.00 (m, 1H), 1.81 (m, 1H), 1.72-1.53 (m, 3H); ¹³CNMR (126 MHz, CDCl₃) δ 208.8, 170.7, 156.5, 136.6, 131.5, 128.6, 128.2,128.1, 119.3, 66.8, 66.4, 62.2, 44.8, 40.9, 33.9, 27.2, 22.1; IR (NeatFilm, NaCl) 3450, 3394, 2943, 1724, 1711, 1509, 1453, 1265 1219, 1141,981 cm⁻¹; HRMS (ESI+) m/z calc'd for C₁₉H₂₄NO₅ [M+H]⁺: 346.1649, found346.1634.

Allyl1-((4-methoxyphenoxy)carbonylaminomethyl)-2-oxocyclohexane-1-carboxylate(3c)

The reaction was conducted according to representative procedure A. Ketoester 1 (182 mg, 1.00 mmol); sulfonylmethyl carbamate 2c (386 mg, 1.20mmol); Cs₂CO₃ (910 mg, 2.50 mmol). The reaction mixture was stirred for24 h. Flash column chromatography (SiO₂, 15% EtOAc in hexanes) affordedα-aminomethyl β-keto ester 3c (265 mg, 0.733 mmol, 73% yield) as acolorless oil. R_(f)=0.18 (20% EtOAc in hexanes); ¹H NMR (500 MHz,CDCl₃) δ 7.01-6.97 (m, 2H), 6.88-6.82 (m, 2H), 5.91 (m, 1H), 5.67 (m,1H), 5.34 (m, 1H), 5.26 (m, 1H), 4.67-4.64 (m, 2H), 3.78 (s, 3H), 3.67(dd, J=13.9, 7.7 Hz, 1H), 3.53 (dd, J=13.9, 5.6 Hz, 1H), 2.62-2.46 (m,3H), 2.03 (m, 1H), 1.84 (m, 1H), 1.76-1.58 (m, 3H); ¹³C NMR (126 MHz,CDCl₃) δ 208.9, 170.7, 157.0, 155.3, 144.7, 131.5, 122.4, 119.4, 114.4,66.5, 62.2, 55.7, 45.0, 40.9, 34.0, 27.2, 22.1; IR (Neat Film, NaCl)3377, 2943, 1742, 1732, 1709, 1498, 1201, 1055 cm⁻¹; HRMS (ESI+) m/zcalc'd for C₁₉H₂₄NO₆ [M+H]⁺: 362.1598, found 362.1601.

Allyl 1-(phenoxycarbonylaminomethyl)-2-oxocyclohexane-1-carboxylate (3d)

The reaction was conducted according to representative procedure A. Ketoester 1 (182 mg, 1.00 mmol); sulfonylmethyl carbamate 2d (350 mg, 1.20mmol); Cs₂CO₃ (910 mg, 2.50 mmol). The reaction mixture was stirred for24 h. Flash column chromatography (SiO₂, 15% EtOAc in hexanes) affordedα-aminomethyl β-keto ester 3d (310 mg, 0.936 mmol, 94% yield) as acolorless oil. R_(f)=0.25 (20% EtOAc in hexanes); ¹H NMR (500 MHz,CDCl₃) δ 7.37-7.29 (m, 2H), 7.18 (m, 1H), 7.12-7.05 (m, 2H), 5.92 (ddt,J=17.3, 10.5, 5.9 Hz, 1H), 5.71 (m, 1H), 5.34 (m, 1H), 5.26 (m, 1H),4.71-4.62 (m, 2H), 3.68 (dd, J=13.9, 7.8 Hz, 1H), 3.53 (dd, J=13.9, 5.6Hz, 1H), 2.64-2.47 (m, 3H), 2.04 (m, 1H), 1.84 (m, 1H), 1.77-1.58 (m,3H); ¹³C NMR (126 MHz, CDCl₃) δ 208.9, 170.7, 154.8, 151.1, 131.5,129.3, 125.4, 121.6, 119.5, 66.5, 62.1, 45.0, 40.9, 34.0, 27.3, 22.1; IR(Neat Film, NaCl) 3377, 2943, 1745, 1728, 1709, 1514, 1489, 1202, 1143cm⁻¹; HRMS (ESI+) m/z calc'd for C₁₈H₂₂NO₅ [M+H]⁺: 332.1492, found332.1483.

Allyl1-((4-fluorophenoxy)carbonylaminomethyl)-2-oxocyclohexane-1-carboxylate(3e)

The reaction was conducted according to representative procedure A. Ketoester 1 (182 mg, 1.00 mmol); sulfonylmethyl carbamate 2e (371 mg, 1.20mmol); Cs₂CO₃ (910 mg, 2.50 mmol). The reaction mixture was stirred for24 h. Flash column chromatography (SiO₂, 15% EtOAc in hexanes) affordedα-aminomethyl β-keto ester 3e (278 mg, 0.796 mmol, 80% yield) as acolorless oil. R_(f)=0.28 (25% EtOAc in hexanes); ¹H NMR (500 MHz,CDCl₃) δ 7.08-6.98 (m, 4H), 5.91 (ddt, J=17.2, 10.5, 5.9 Hz, 1H), 5.72(m, 1H), 5.34 (m, 1H), 5.26 (m, 1H), 4.68-4.60 (m, 2H), 3.67 (dd,J=13.9, 7.8 Hz, 1H), 3.52 (dd, J=13.9, 5.5 Hz, 1H), 2.64-2.46 (m, 3H),2.04 (m, 1H), 1.83 (m, 1H), 1.76-1.57 (m, 3H); ¹³C NMR (126 MHz, CDCl₃)δ 208.9, 170.7, 160.0 (J=243 Hz), 154.8, 147.0 (J=4 Hz), 131.4, 123.0(J=9 Hz), 119.5, 115.9 (J=23 Hz), 66.6, 62.1, 45.1, 40.9, 34.0, 27.3,22.1; IR (Neat Film, NaCl) 3377, 2944, 1746, 1732, 1711, 1497, 1219,1193, 1147 cm⁻¹; HRMS (ESI+) m/z calc'd for C₁₈H₂₁FNO₅ [M+H]⁺: 350.1398,found 350.1392.

Allyl 1-(benzamidomethyl)-2-oxocyclohexane-1-carboxylate (3f)

The reaction was conducted according to representative procedure A. Ketoester 1 (182 mg, 1.00 mmol); sulfonylmethyl carbamate 2f (413 mg, 1.50mmol); Cs₂CO₃ (977 mg, 3.0 mmol). The reaction mixture was stirred for24 h. Flash column chromatography (SiO₂, 15% EtOAc in hexanes) affordedα-aminomethyl β-keto ester 3f (250 mg, 0.793 mmol, 79% yield) as a whiteamorphous solid. R_(f)=0.30 (40% EtOAc in hexanes); ¹H NMR (500 MHz,CDCl₃) δ 7.72-7.67 (m, 2H), 7.49-7.44 (m, 1H), 7.42-7.36 (m, 2H),6.96-6.87 (m, 1H), 5.83 (ddt, J=17.2, 10.4, 6.0 Hz, 1H), 5.27 (dq,J=17.1, 1.4 Hz, 1H), 5.18 (dq, J=10.4, 1.2 Hz, 1H), 4.65-4.52 (m, 2H),3.96 (dd, J=13.6, 7.7 Hz, 1H), 3.65 (dd, J=13.6, 5.2 Hz, 1H), 2.61-2.49(m, 3H), 2.05-1.97 (m, 1H), 1.87-1.81 (m, 1H), 1.75-1.58 (m, 3H); ¹³CNMR (126 MHz, CDCl₃) δ 209.5, 170.8, 167.4, 134.4, 131.6, 131.4, 128.6,127.0, 119.5, 66.6, 62.2, 43.3, 40.9, 34.2, 27.2, 22.1; IR (Neat Film,NaCl) 3447, 3356, 3061, 3028, 2943, 2866, 1712, 1667, 1651, 1602, 1580,1519, 1488, 1450, 1307, 1280, 1203, 1142 cm⁻¹; HRMS (ESI+) m/z calc'dfor C₁₈H₂₂NO₄ [M+H]⁺: 316.1543, found 316.1559.

Allyl1-(((4-methylphenyl)sulfonamido)methyl)-2-oxocyclohexane-1-carboxylate(3g)

The reaction was conducted according to representative procedure A. Ketoester 1 (182 mg, 1.00 mmol); sulfonylmethyl carbamate 2g (488 mg, 1.50mmol); Cs₂CO₃ (977 mg, 3.0 mmol). The reaction mixture was stirred for24 h. Flash column chromatography (SiO₂, 25% EtOAc in hexanes) affordedα-aminomethyl β-keto ester 3g (365 mg, 0.999 mmol, >99% yield) as aclear colorless oil. R_(f)=0.25 (25% EtOAc in hexanes); ¹H NMR (500 MHz,CDCl₃) δ 7.73-7.69 (m, 2H), 7.30 (dd, J=8.4, 1.0 Hz, 2H), 5.88 (ddt,J=17.2, 10.4, 5.9 Hz, 1H), 5.32 (dq, J=17.2, 1.5 Hz, 1H), 5.27 (dq,J=10.4, 1.2 Hz, 1H), 5.20 (dd, J=8.3, 5.8 Hz, 1H), 4.61 (dt, J=5.9, 1.3Hz, 2H), 3.21 (dd, J=12.5, 8.4 Hz, 1H), 3.06 (dd, J=12.5, 5.8 Hz, 1H),2.65-2.56 (m, 1H), 2.46-2.36 (m, 4H), 2.06-1.97 (m, 1H), 1.82-1.76 (m,1H), 1.72-1.58 (m, 4H); ¹³C NMR (126 MHz, CDCl₃) δ 209.0, 170.4, 143.6,137.0, 131.4, 129.9, 127.1, 119.6, 66.6, 61.6, 47.2, 40.9, 34.1, 27.0,22.1, 21.7; IR (Neat Film, NaCl) 3289, 2942, 2867, 1728, 1709, 1451,1335, 1206, 1163, 1092 cm⁻¹; HRMS (FAB+) m/z calc'd for C₁₈H₂₄NO₅S[M+H]⁺: 366.1375, found 366.1367.

2-Phenylallyl1-(((tert-butoxycarbonyl)amino)methyl)-2-oxocyclohexane-1-carboxylate(6a)

The reaction was conducted according to representative procedure A. Ketoester 5a (311 mg, 1.2 mmol); sulfonylmethyl carbamate 2a (392 mg, 1.44mmol); Cs₂CO₃ (977 mg, 3.0 mmol). The reaction mixture was stirred for24 h. Flash column chromatography (SiO₂, 15% EtOAc in hexanes) affordedα-aminomethyl β-keto ester 6a (368 mg, 0.95 mmol, 79% yield) as a paleyellow oil. R_(f)=0.5 (25% EtOAc in hexanes); ¹H NMR (500 MHz, CDCl₃) δ7.42-7.38 (m, 2H), 7.36-7.32 (m, 2H), 7.31-7.27 (m, 1H), 5.53 (d, J=0.9Hz, 1H), 5.37 (q, J=1.1 Hz, 1H), 5.1 (d, J=13.0 Hz, 1H), 5.07 (t, J=7.0Hz, 1H), 5.01 (d, J=13.0, 1H), 3.48 (dd, J=13.9, 7.6 Hz, 1H), 3.35 (dd,J=13.9, 5.8 Hz, 1H), 2.38-2.27 (m, 2H), 2.26-2.18 (m, 1H), 1.81 (m, 1H),1.69-1.63 (m, 1H), 1.60-1.50 (m, 1H), 1.49-1.41 (m, 2H), 1.39 (s, 9H);¹³C NMR (126 MHz, CDCl₃) δ 208.7, 170.8, 155.0, 142.4, 137.9, 128.7,128.3, 126.3, 116.3, 79.4, 66.9, 62.3, 44.3, 40.6, 33.7, 28.4, 27.2,21.9; IR (Neat Film, NaCl) 3458, 3411, 2975, 2938, 2866, 1715, 1499,1365, 1167, 1141 cm⁻¹; HRMS (ESI+) m/z calc'd for C₂₂H₂₉NO₅Na [M+Na]⁺:410.1938, found 410.1923.

Allyl 1-(t-butoxycarbonylaminomethyl)-2-oxocycloheptane-1-carboxylate(6b)

The reaction was conducted according to representative procedure A. Ketoester 5b (196 mg, 1.00 mmol); sulfonylmethyl carbamate 2a (326 mg, 1.20mmol); Cs₂CO₃ (815 mg, 2.50 mmol). The reaction mixture was stirred for24 h. Flash column chromatography (SiO₂, 15% EtOAc in hexanes) affordedα-aminomethyl β-keto ester 6b (234 mg, 0.719 mmol, 72% yield) as acolorless oil. R_(f)=0.47 (20% EtOAc in hexanes); ¹H NMR (500 MHz,CDCl₃) δ 5.90 (m, 1H), 5.32 (m, 1H), 5.25 (m, 1H), 5.18 (m, 1H),4.68-4.56 (m, 2H), 3.56 (dd, J=14.0, 7.7 Hz, 1H), 3.50 (dd, J=14.0, 5.8Hz, 1H), 2.68 (m, 1H), 2.56 (ddd, J=13.0, 8.3, 3.3 Hz, 1H), 2.08 (m,1H), 1.86-1.76 (m, 2H), 1.73-1.48 (m, 5H), 1.40 (s, 9H); ¹³C NMR (126MHz, CDCl₃) δ 210.2, 171.7, 156.1, 131.7, 119.0, 79.4, 66.2, 63.9, 45.3,42.7, 31.7, 30.1, 28.4, 25.7, 25.3; IR (Neat Film, NaCl) 3461, 2976,2933, 1718, 1501, 1456, 1366, 1248m 1225, 1169 cm⁻¹; HRMS (ESI+) m/zcalc'd for C₁₇H₂₇NO₅Na [M+Na]⁺: 348.1781, found 348.1772.

Allyl 1-(t-butoxycarbonylaminomethyl)-2-oxocyclopentane-1-carboxylate(6c)

The reaction was conducted according to representative procedure A. Ketoester 5c (168 mg, 1.00 mmol); sulfonylmethyl carbamate 2a (326 mg, 1.20mmol); Cs₂CO₃ (815 mg, 2.50 mmol). The reaction mixture was stirred for24 h. Flash column chromatography (SiO₂, 15% EtOAc in hexanes) affordedα-aminomethyl β-keto ester 6c (255 mg, 0.858 mmol, 86% yield) as acolorless oil. R_(f)=0.50 (33% EtOAc in hexanes); ¹H NMR (500 MHz,CDCl₃) δ 5.87 (ddt, J=17.2, 10.4, 5.6 Hz, 1H), 5.29 (m, 1H), 5.24 (m,1H), 5.13 (m, 1H), 4.67-4.55 (m, 2H), 3.50 (dd, J=14.0, 7.0 Hz 1H), 3.46(dd, J=14.0, 6.0 Hz, 1H), 2.49-2.34 (m, 3H), 2.16-1.98 (m, 3H), 1.42 (s,9H); ¹³C NMR (126 MHz, CDCl₃) δ 213.7, 171.3, 156.3, 131.5, 118.8, 79.7,66.1, 61.5, 42.1, 38.2, 31.7, 28.4, 19.8; IR (Neat Film, NaCl) 3394,2976, 1749, 1715, 1504, 1454, 1366, 1249, 1229, 1168, 966 cm⁻¹; HRMS(ESI+) m/z calc'd for C₁₅H₂₃NO₅Na [M+Na]⁺: 320.1468, found 320.1467.

Allyl1-(((tert-butoxycarbonyl)amino)methyl)-4-isobutoxy-2-oxocyclohept-3-ene-1-carboxylate(6d)

The reaction was conducted according to representative procedure A. Ketoester 5d (100 mg, 0.375 mmol); sulfonylmethyl carbamate 2a (122 mg, 0.45mmol); Cs₂CO₃ (305 mg, 0.936 mmol). The reaction mixture was stirred for10 h. Flash column chromatography (SiO₂, 15% EtOAc in hexanes) affordedα-aminomethyl β-keto ester 6d (123 mg, 0.311 mmol, 83% yield) as a clearoil. R_(f)=0.5 (25% EtOAc in hexanes); ¹H NMR (500 MHz, CDCl₃) δ 5.87(ddt, J=17.3, 10.5, 5.7 Hz, 1H), 5.38 (s, 1H), 5.29 (dq, J=17.2, 1.6 Hz,1H), 5.27 (m, 1H), 5.21 (dq, J=10.5, 1.3 Hz, 1H), 4.63 (ddt, J=13.2,5.9, 1.4 Hz, 1H), 4.56 (ddt, J=13.3, 5.8, 1.4 Hz, 1H), 3.64 (dd, J=13.7,7.8 Hz, 1H), 3.51-3.44 (m, 3H), 2.55 (ddd, J=17.9, 10.0, 4.2 Hz, 1H),2.44 (ddd, J=17.8, 7.1, 3.8 Hz, 1H), 2.36 (m, 1H), 2.03-1.94 (m, 2H),1.89-1.76 (m, 2H), 1.40 (s, 9H), 0.94 (dd, J=6.7, 1.5 Hz, 6H); ¹³C NMR(126 MHz, CDCl₃) δ 198.1, 174.9, 172.1, 156.1, 131.7, 118.8, 105.3,79.3, 74.9, 66.2, 63.9, 46.4, 34.2, 29.3, 28.5, 27.9, 21.3, 19.2; IR(Neat Film, NaCl) 3459, 3394, 3083, 2961, 2934, 2874, 1734, 1718, 1636,1610, 1499, 1388, 1366, 1232, 1171 cm⁻¹; HRMS (ESI+) m/z calc'd forC₂₁H₃₃NO₆Na [M+Na]⁺: 418.2200, found 418.2192.

Allyl2-(((tert-butoxycarbonyl)amino)methyl)-1-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylate(6e)

The reaction was conducted according to representative procedure A. Ketoester 5e (230.3 mg, 1.0 mmol); sulfonylmethyl carbamate 2a (326 mg, 1.2mmol); Cs₂CO₃ (815 mg, 2.5 mmol). The reaction mixture was stirred for24 h. Flash column chromatography (SiO₂, 15% EtOAc in hexanes) affordedα-aminomethyl β-keto ester 6e (395 mg, 0.999 mmol, >99% yield) as a paleyellow oil. R_(f)=0.5 (25% EtOAc in hexanes); ¹H NMR (500 MHz, CDCl₃) δ8.03 (dd, J=8.0, 1.4 Hz, 1H), 7.49 (td, J=7.5, 1.5 Hz, 1H), 7.34-7.29(m, 1H), 7.23 (dq, J=7.8, 0.7 Hz, 1H), 5.86-5.76 (m, 1H), 5.33-5.27 (m,1H), 5.22-5.14 (m, 2H), 4.61 (dt, J=2.4, 1.4 Hz, 1H), 4.59 (dt, J=2.4,1.4 Hz, 1H), 3.79 (dd, J=13.9, 7.9 Hz, 1H), 3.56 (dd, J=13.9, 5.4 Hz,1H), 3.10 (dt, J=17.5, 5.4 Hz, 1H), 3.02 (ddd, J=17.4, 9.4, 4.8 Hz, 1H),2.57 (dt, J=13.8, 5.3 Hz, 1H), 2.20 (ddd, J=14.1, 9.5, 5.0 Hz, 1H), 1.41(s, 9H); ¹³C NMR (126 MHz, CDCl₃) δ 195.6, 171.0, 156.1, 143.4, 134.1,131.9, 131.5, 129.0, 128.0, 127.0, 118.7, 79.5, 66.1, 59.4, 43.6, 29.3,28.5, 25.8; IR (Neat Film, NaCl) 3454, 3395, 2977, 2934, 1731, 1717,1683, 1601, 1505, 1456, 1366, 1235, 1170 cm⁻¹; HRMS (FAB+) m/z calc'dfor C₂₀H₂₆NO₅ [M+H]⁺: 360.1811, found 360.1801.

Allyl1-benzyl-3-(((tert-butoxycarbonyl)amino)methyl)-4-oxopiperidine-3-carboxylate(6f)

The reaction was conducted according to representative procedure A. Ketoester 5f (296 mg, 1.08 mmol); sulfonylmethyl carbamate 2a (353 mg, 1.296mmol); Cs₂CO₃ (882 mg, 2.7 mmol). The reaction mixture was stirred for24 h. Flash column chromatography (SiO₂, 15% EtOAc in hexanes) affordedα-aminomethyl β-keto ester 6f (349 mg, 0.867 mmol, 80% yield) as a clearcolorless oil. R_(f)=0.45 (25% EtOAc in hexanes); ¹H NMR (500 MHz, C₆D₆)δ 7.20-7.12 (m, 4H), 7.11-7.05 (m, 1H), 5.71 (ddt, J=16.5, 10.9, 5.7 Hz,1H), 5.37 (t, J=6.8 Hz, 1H), 5.09 (dd, J=17.2, 1.6 Hz, 1H), 4.94 (dq,J=10.4, 1.3 Hz, 1H), 4.47 (d, J=5.8, 1.4 Hz, 2H), 3.63 (dd, J=13.9, 6.0Hz, 1H), 3.57 (dd, J=13.9, 7.4 Hz, 1H), 3.23-3.20 (m, 1H), 3.19 (d,J=13.5 Hz, 1H), 3.10 (d, J=13.4 Hz, 1H), 2.65 (ddd, J=14.3, 10.0, 6.7Hz, 1H), 2.37-2.29 (m, 2H), 1.99 (d, J=11.6, 1H), 1.93-1.87 (m, 1H),1.37 (s, 9H); ¹³C NMR (126 MHz, C₆D₆) δ 205.9, 170.5, 155.9, 138.3,132.2, 129.0, 128.7, 127.6, 118.4, 79.0, 66.1, 62.9, 61.9, 58.9, 53.1,43.0, 40.3, 28.4; IR (Neat Film, NaCl) 3457, 2976, 2925, 2811, 1718,1499, 1366, 1250, 1225, 1169 cm⁻¹; HRMS (FAB+) m/z calc'd for C₂₂H₃₁N₂O₅[M+H]⁺: 403.2233, found 403.2238.

Allyl1-benzoyl-3-(tert-butoxycarbonylaminomethyl)-2-oxopiperidine-3-carboxylate(6g)

The reaction was conducted according to representative procedure A.Amido ester 5g (231 mg, 0.800 mmol); sulfonylmethyl carbamate 2a (261mg, 0.960 mmol); Cs₂CO₃ (652 mg, 2.00 mmol). The reaction mixture wasstirred for 24 h. Flash column chromatography (SiO₂, 15→20% EtOAc inhexanes) afforded α-aminomethyl amido ester 6g (245 mg, 0.588 mmol, 74%yield) as a colorless oil. R_(f)=0.36 (33% EtOAc in hexanes); ¹H NMR(500 MHz, CDCl₃) δ 7.81-7.74 (m, 2H), 7.50 (m, 1H), 7.44-7.36 (m, 2H),5.97 (ddt, J=16.6, 10.4, 6.0 Hz, 1H), 5.40 (m, 1H), 5.33 (m, 1H), 5.15(m, 1H), 4.82-4.63 (m, 2H), 3.91-3.74 (m, 2H), 3.71 (dd, J=13.9, 7.5 Hz,1H), 3.50 (dd, J=13.9, 5.9 Hz, 1H), 2.43 (m, 1H), 2.12-1.91 (m, 3H),1.41 (s, 9H); ¹³C NMR (126 MHz, CDCl₃) δ 174.9, 172.2, 170.7, 156.1,135.6, 132.1, 131.3, 128.3, 128.3, 119.9, 79.7, 66.8, 58.4, 46.8, 44.7,29.1, 28.4, 20.0; IR (Neat Film, NaCl) 3446, 2976, 1714, 1684, 1500,1449, 1391, 1366, 1271, 1249, 1164, 1141, 939 cm⁻¹; HRMS (ESI+) m/zcalc'd for C₂₂H₂₈N₂O₆Na [M+Na]⁺: 439.1840, found 439.1854.

Allyl4-benzoyl-2-(tert-butoxycarbonylaminomethyl)-3-oxomorpholine-2-carboxylate(6h)

The reaction was conducted according to representative procedure A.Morpholinone 5h (100 mg, 0.346 mmol); sulfonylmethyl carbamate 2a (188mg, 0.691 mmol); Cs₂CO₃ (338 mg, 1.04 mmol). The reaction mixture wasstirred for 24 h. Flash column chromatography (SiO₂, 20→25% EtOAc inhexanes) afforded α-aminomethyl morpholinone 6h (132 mg, 0.315 mmol, 91%yield) as a colorless oil. R_(f)=0.34 (10% EtOAc in toluene); ¹H NMR(500 MHz, CDCl₃) δ 7.67-7.65 (m, 2H), 7.52 (m, 1H), 7.43-7.38 (m, 2H),5.97 (m, 1H), 5.41 (m, 1H), 5.33 (m, 1H), 5.00 (brs, 1H), 4.76-4.73 (m,2H), 4.30-4.17 (m, 2H), 4.05-3.90 (m, 2H), 3.87-3.72 (m, 2H), 1.42 (s,9H); ¹³C NMR (126 MHz, CDCl₃) δ 172.7, 167.7, 167.5, 155.8, 134.7,132.5, 131.0, 128.5, 128.3, 119.9, 83.1, 79.9, 67.2, 62.1, 45.0, 44.8,28.4; IR (Neat Film, NaCl) 3388, 2977, 2934, 1746, 1714, 1693, 1507,1449, 1367, 1317, 1279, 1233, 1165, 1066, 944, 757, 727, 693 cm⁻¹; HRMS(ESI+) m/z calc'd for C₂₁H₂₆N₂O₇Na [M+Na]⁺: 441.1632, found 441.1636.

Allyl3-(((tert-butoxycarbonyl)amino)methyl)-4-oxo-9-tosyl-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylate(6i)

The reaction was conducted according to representative procedure A. Ketoester 5i (400 mg, 0.994 mmol); sulfonylmethyl carbamate 2a (307 mg, 1.13mmol); Cs₂CO₃ (770 mg, 2.36 mmol). The reaction mixture was stirred for24 h. Flash column chromatography (SiO₂, 15% EtOAc in hexanes) affordedα-aminomethyl β-keto ester 6i (418 mg, 0.756 mmol, 80% yield) as a clearcolorless oil. R_(f)=0.33 (25% EtOAc in hexanes); ¹H NMR (500 MHz,CDCl₃) δ 8.21-8.17 (m, 1H), 8.15-8.12 (m, 1H), 7.78 (d, J=8.4 Hz, 2H),7.38-7.31 (m, 2H), 7.27 (d, J=8.4 Hz, 2H), 5.80 (m, 1H), 5.25-5.17 (m,2H), 5.15 (m, 1H), 4.58 (dt, J=5.8, 1.4 Hz, 2H), 3.74 (dd, J=14.0, 7.7Hz, 1H), 3.59 (m, 2H), 3.41 (ddd, J=19.2, 8.3, 5.2 Hz, 1H), 2.67 (dt,J=13.9, 5.4 Hz, 1H), 2.37 (s, 3H), 2.28 (m, 1H), 1.42 (s, 9H); ¹³C NMR(126 MHz, CDCl₃) δ 191.4, 170.6, 156.1, 150.7, 146.1, 136.2, 135.3,131.5, 130.4, 126.9, 125.8, 125.7, 125.2, 121.9, 118.9, 117.1, 114.0,79.6, 66.2, 59.3, 43.3, 29.2, 28.5, 22.1, 21.8; IR (Neat Film, NaCl)3445, 3054, 2977, 2933, 2254, 1733, 1713, 1596, 1558, 1505, 1481, 1451,1410, 1380, 1244, 1174, 1090 cm⁻¹; HRMS (ESI+) m/z calc'd forC₂₉H₃₃N₂O₇S [M+H]⁺: 553.2003, found 553.1994.

Example 2. Representative Procedure for Palladium-Catalyzed AllylicAlkylation

With β-keto esters 3a-g in hand, this substrate class was investigatedin the context of palladium-catalyzed allylic alkylation as shown inTable 1. Exposure of Boc-protected substrate 3a to a catalyticphosphinooxazolinepalladium(0) complex in toluene at ambient temperatureafforded the desired product 4a in 94% yield and 86% ee (entry 1).Cbz-protected 3b also gave excellent yield and ee (entry 2). It isimportant to note that no N-alkylated side products were detected, aresult that highlights the mild nature of these reaction conditions.Arylcarbamates 3c-e gave slightly decreased enantioselectivities in theproducts (entries 3-5). We also examined benzoyl and tosyl protectinggroups.

TABLE 1 Optimization of the Amine Protecting Group.^(a)

entry R (3 → 4) yield (%) ee (%)^(b) 1 Boc (3a → 4a) 94 86 2 Cbz (3b →4b) 96 86 3 4 5

X = OMe (3c → 4c) X = H (3d → 4d) X = F (3e → 4e) 91 90 84 83 77 77 6 Bz(3f → 4f) ND^(c) 56 7 Ts (3g → 4g) 54 24

^(a)Reaction performed with 0.2 mmol of 3, 5 mol % of Pd₂(dba)₃ (dba =dibenzylideneacetone), 12.5 mol % of (S)—(CF₃)₃-t-BuPHOX L1 at 0.033 Min toluene at 23° C. ^(b)Determined by chiral SFC analysis. Absolutestereochemistry has been assigned by analogy, except in entry 2, whichwas assigned by conversion into (−)-isonitramine. ^(c)A yield was notdetermined.

Please note that the absolute configuration of all products 4 and 7 hasbeen inferred from previous studies (Behenna, D. C., et al., Chem. Eur.J. 2011, 17, 14199-14223), with the exception of 4b, which was assignedby conversion to (−)-isonitramine.

Representative Procedure B

(S)-Tert-butyl ((1-allyl-2-oxocyclohexyl)methyl)carbamate (4a). In anitrogen-filled glove box, [Pd₂(dba)₃] (9.2 mg, 0.010 mmol, 0.05 equiv)and (S)-(CF₃)₃-t-BuPHOX L1 (14.8 mg, 0.025 mmol, 0.125 equiv) were addedto a 20 mL scintillation vial equipped with a magnetic stirring bar. Thevial was then charged with toluene (4.1 mL) and stirred at 25° C. for 30min, generating a yellow solution. To the preformed catalyst solutionwas added a solution of 3a (62.3 mg, 0.20 mmol, 1 equiv) in toluene (2.0mL). The vial was sealed and stirred at 25° C. until the fullconsumption of β-keto ester 3a was observed by TLC analysis. Thereaction mixture was concentrated in vacuo. Flash column chromatography(SiO₂, 2% EtOAc in CH₂Cl₂ eluent) afforded α-quaternary ketone 4a (50.2mg, 94% yield) as a colorless oil. 86% ee, [α]_(D) ²⁵−25.5 (c 0.865,C₆H₆); R_(f)=0.55 (5% EtOAc in DCM); ¹H NMR (500 MHz, C₆D₆) δ 5.64 (m,1H), 5.05 (br t, J=6.4 Hz, 1H), 4.94 (ddt, J=10.1, 2.0, 1.0 Hz, 1H),4.87 (dq, J=17.0, 1.5 Hz, 1H), 3.30 (dd, J=13.9, 7.2 Hz, 1H), 3.24 (dd,J=13.9, 6.1 Hz, 1H), 2.15-2.08 (m, 2H), 2.01-1.91 (m, 2H), 1.44 (s, 9H),1.41-1.30 (m, 2H), 1.25-1.12 (m, 2H); ¹³C NMR (126 MHz, C₆D₆) δ 213.5,156.2, 133.3, 118.5, 78.7, 53.1, 45.2, 39.1, 37.9, 33.7, 28.5, 27.1,20.6; IR (Neat Film, NaCl) 3462, 3395, 2977, 2939, 2867, 1718, 1499,1167 cm⁻¹; HRMS (ESI+) m/z calc'd for C₁₅H₂₅NO₃Na [M+Na]⁺: 290.1727,found 290.1718; SFC conditions: 10% IPA, 2.5 mL/min, Chiralpak AD-Hcolumn, λ=210 nm, t_(R) (min): major=7.65, minor=8.46.

Spectroscopic Data for Exemplary Alkylation Products (S)-Benzyl(1-allyl-2-oxocyclohexyl)methylcarbamate (4b)

The reaction was conducted according to representative procedure B. Ketoester 3b (69.1 mg, 0.200 mmol). The reaction mixture was stirred at 23°C. for 14 h. Flash column chromatography (SiO₂, 10→15% EtOAc in hexanes)afforded ketone 4b (57.7 mg, 0.191 mmol, 96% yield) as a colorless oil.86% ee, [α]_(D) ²⁵−38.6 (c 1.20, CHCl₃); R_(f)=0.44 (25% EtOAc inhexanes); ¹H NMR (300 MHz, CDCl₃) δ 7.42-7.25 (m, 5H), 5.67 (m, 1H),5.21 (m, 1H), 5.16-5.00 (m, 4H), 3.34 (dd, J=13.9, 5.9 Hz, 1H), 3.24(dd, J=13.9, 7.4 Hz, 1H), 2.54-2.20 (m, 4H), 1.99 (m, 1H), 1.81-1.60 (m,5H); ¹³C NMR (126 MHz, CDCl₃) δ 215.5, 156.9, 136.7, 132.2, 128.6,128.2, 128.1, 119.2, 66.8, 53.2, 45.4, 39.3, 38.0, 33.7, 27.2, 20.6.; IR(Neat Film, NaCl) 3351, 2937, 1722, 1702, 1510, 1454, 1234, 1134 cm⁻¹;HRMS (ESI+) m/z calc'd for C₁₈H₂₄NO₃ [M+H]⁺: 302.1751, found 302.1756;SFC conditions: 5% IPA, 2.5 mL/min, Chiralpak AD-H column, λ=210 nm,t_(R) (min): major=8.12, minor=9.06.

(S)-4-methoxyphenyl (1-allyl-2-oxocyclohexyl)methylcarbamate (4c)

The reaction was conducted according to representative procedure B. Ketoester 3c (72.3 mg, 0.200 mmol). The reaction mixture was stirred at 23°C. for 24 h. Flash column chromatography (SiO₂, 15→20% EtOAc in hexanes)afforded ketone 4c (57.6 mg, 0.181 mmol, 91% yield) as a colorless oil.83% ee, [α]_(D) ²⁵−29.3 (c 0.76, CHCl₃); R_(f)=0.25 (25% EtOAc inhexanes); ¹H NMR (500 MHz, CDCl₃) δ 7.05-6.97 (m, 2H), 6.90-6.81 (m,2H), 5.70 (m, 1H), 5.49 (m, 1H), 5.18-5.09 (m, 2H), 3.78 (s, 3H), 3.40(dd, J=13.9, 6.0 Hz, 1H), 3.28 (dd, J=13.9, 7.2 Hz, 1H), 2.55-2.44 (m,2H), 2.41-2.28 (m, 2H), 2.03 (m, 1H), 1.90-1.64 (m, 5H); ¹³C NMR (126MHz, CDCl₃) δ 215.6, 157.0, 155.6, 144.8, 132.2, 122.5, 119.3, 114.4,55.7, 53.2, 45.6, 39.4, 38.0, 33.8, 27.3, 20.6; IR (Neat Film, NaCl)3345, 2937, 1740, 1700, 1501, 1201 cm⁻¹; HRMS (ESI+) m/z calc'd forC₁₈H₂₄NO₄ [M+H]⁺: 318.1700, found 318.1705; SFC conditions: 10% IPA, 2.5mL/min, Chiralcel OB-H column, λ=210 nm, t_(R) (min): major=9.47,minor=11.13.

(S)-phenyl (1-allyl-2-oxocyclohexyl)methylcarbamate (4d)

The reaction was conducted according to representative procedure B. Ketoester 3d (66.3 mg, 0.200 mmol). The reaction mixture was stirred at 23°C. for 24 h. Flash column chromatography (SiO₂, 10→15% EtOAc in hexanes)afforded ketone 4d (51.5 mg, 0.179 mmol, 90% yield) as a colorless oil.77% ee, [α]_(D) ²⁵−28.9 (c 0.40, CHCl₃); R_(f)=0.29 (25% EtOAc inhexanes); ¹H NMR (500 MHz, CDCl₃) δ 7.34 (t, J=7.7 Hz, 2H), 7.17 (m,1H), 7.11 (d, J=8.0 Hz, 2H), 5.70 (m, 1H), 5.53 (m, 1H), 5.20-5.11 (m,2H), 3.41 (dd, J=14.0, 6.0 Hz, 1H), 3.29 (dd, J=14.0, 7.2 Hz, 1H),2.55-2.45 (m, 2H), 2.42-2.29 (m, 2H), 2.03 (m, 1H), 1.90-1.65 (m, 5H);¹³C NMR (126 MHz, CDCl₃) δ 215.7, 155.1, 151.2, 132.1, 129.3, 125.3,121.6, 119.4, 53.2, 45.6, 39.4, 38.0, 33.8, 27.3, 20.6; IR (Neat Film,NaCl) 3346, 2937, 1743, 1701, 1490, 1203 cm⁻¹; HRMS (ESI+) m/z calc'dfor C₁₇H₂₂NO₃ [M+H]⁺: 288.1594, found 288.1589; SFC conditions: 10% IPA,2.5 mL/min, Chiralcel OB-H column, λ=210 nm, t_(R) (min): major=6.53,minor=8.13.

(S)-4-fluorophenyl (1-allyl-2-oxocyclohexyl)methylcarbamate (4e)

The reaction was conducted according to representative procedure B. Ketoester 3e (69.9 mg, 0.200 mmol). The reaction mixture was stirred at 23°C. for 24 h. Flash column chromatography (SiO₂, 10→15% EtOAc in hexanes)afforded ketone 4e (51.4 mg, 0.168 mmol, 84% yield) as a colorless oil.77% ee, [α]_(D) ²⁵−27.4 (c 0.78, CHCl₃); R_(f)=0.37 (25% EtOAc inhexanes); ¹H NMR (500 MHz, CDCl₃) δ 7.10-6.97 (m, 4H), 5.69 (m, 1H),5.54 (m, 1H), 5.17-5.10 (m, 2H), 3.40 (dd, J=13.9, 6.0 Hz, 1H), 3.27(dd, J=13.9, 7.2 Hz, 1H), 2.55-2.45 (m, 2H), 2.41-2.29 (m, 2H), 2.04 (m,1H), 1.91-1.63 (m, 5H); ¹³C NMR (126 MHz, CDCl₃) δ 215.7, 160.0 (J=243Hz), 155.1, 147.1 (J=4 Hz), 132.1, 123.1 (J=7 Hz), 119.4, 115.9 (J=24Hz), 53.2, 45.6, 39.4, 37.9, 33.8, 27.3, 20.6; IR (Neat Film, NaCl)3347, 2938, 1742, 1699, 1498, 1192 cm⁻¹; HRMS (ESI+) m/z calc'd forC₁₇H₂₁FNO₃ [M+H]⁺: 306.1500, found 306.1493; SFC conditions: 10% IPA,2.5 mL/min, Chiralpak AS-H column, λ=210 nm, t_(R) (min): major=6.94,minor=8.24.

(S)-N-((1-allyl-2-oxocyclohexyl)methyl)benzamide (4f)

The reaction was conducted according to representative procedure B. Ketoester 3f (19.1 mg, 0.60 mmol). The reaction mixture was stirred at 23°C. for 20 h. Flash column chromatography (SiO₂, 10→15% EtOAc in hexanes)afforded ketone 4f as a colorless oil. 56% ee, R_(f)=0.23 (25% EtOAc inhexanes); ¹H NMR (500 MHz, CDCl₃) δ 7.76-7.72 (m, 2H), 7.49 (m, 1H),7.45-7.40 (m, 2H), 6.78 (m, 1H), 5.66 (m, 1H), 5.15 (d, J=1.2 Hz, 1H),5.12 (m, 1H), 3.58 (dd, J=13.8, 6.1 Hz, 1H), 3.55 (dd, J=13.8, 6.1 Hz,1H), 2.56-2.47 (m, 2H), 2.40-2.32 (m, 2H), 2.03 (m, 1H), 1.92-1.79 (m,2H), 1.77-1.61 (m, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 216.6, 167.5, 134.7,132.3, 131.6, 128.7, 127.0, 119.4, 53.5, 43.9, 39.5, 38.3, 34.1, 27.4,20.6; IR (Neat Film, NaCl) 3439, 3338, 3070, 2936, 2864, 1693, 1668,1649, 1535, 1515, 1486, 1454, 1286, 1127 cm⁻¹; HRMS (ESI/APCI) m/zcalc'd for C₁₇H₂₂NO₂ [M+H]⁺: 272.1645, found 272.1638; SFC conditions:20% IPA, 2.5 mL/min, Chiralpak AD-H column, λ=210 nm, t_(R) (min):major=4.04, minor=4.91.

(S)-N-((1-allyl-2-oxocyclohexyl)methyl)-4-methylbenzenesulfonamide (4g)

The reaction was conducted according to representative procedure B. Ketoester 3g (74.0 mg, 0.202 mmol). The reaction mixture was stirred at 23°C. for 20 h. Flash column chromatography (SiO₂, 15% EtOAc in hexanes)afforded ketone 4g (35.3 mg, 0.109 mmol, 54% yield) as a yellow oil. 24%ee, R_(f)=0.3 (25% EtOAc in hexanes); ¹H NMR (500 MHz, CDCl₃) δ 7.71 (m,2H), 7.30 (dd, J=8.3, 0.9 Hz, 2H), 5.61 (dddd, J=16.3, 10.8, 7.9, 6.9Hz, 1H), 5.11-5.06 (m, 3H), 2.97 (dd, J=12.6, 6.7 Hz, 1H), 2.70 (dd,J=12.6, 7.5 Hz, 1H), 2.50-2.43 (m, 2H), 2.41 (s, 3H), 2.31-2.21 (m, 2H),2.01 (m, 1H), 1.84-1.55 (m, 5H); ¹³C NMR (126 MHz, CDCl₃) δ 215.7,143.4, 137.0, 131.5, 129.9, 127.0, 119.7, 52.5, 47.7, 39.2, 37.4, 33.4,27.1, 21.6, 20.5; IR (Neat Film, NaCl) 3285, 3071, 2938, 2865, 1919,1762, 1703, 1638, 1598, 1495, 1454, 1333, 1164, 1091 cm⁻¹; HRMS (ESI+)m/z calc'd for C₁₇H₂₄NO₃S [M+H]⁺: 322.1471, found 322.1456; SFCconditions: 15% IPA, 2.5 mL/min, Chiralcel OJ-H column, λ=210 nm, t_(R)(min): major=3.14, minor=3.85.

(S)-tert-butyl ((2-oxo-1-(2-phenylallyl)cyclohexyl)methyl)carbamate (7a)

The reaction was conducted according to representative procedure B. Ketoester 6a (110 mg, 0.284 mmol); [Pd₂(pmdba)₃] (15.6 mg, 0.014 mmol, 0.05equiv). The reaction mixture was stirred at 23° C. for 24 h. Flashcolumn chromatography (SiO₂, 20% acetone in hexanes) afforded ketone 7a(88.7 mg, 0.258 mmol, 91% yield) as a yellow oil. 90% ee, [α]_(D)²⁵−30.9 (c 4.45, CHCl₃); R_(f)=0.55 (25% EtOAc in hexanes); ¹H NMR (500MHz, CDCl₃) δ 7.32-7.26 (m, 5H), 5.23 (d, J=1.4 Hz, 1H), 5.08 (d, J=2.0Hz, 1H), 4.67 (dd, J=8.3, 4.4 Hz, 1H), 3.16 (dd, J=14.0, 8.5 Hz, 1H),3.09 (dd, J=13.9, 4.7 Hz, 1H), 2.99 (d, J=14.1 Hz, 1H), 2.71 (d, J=14.1Hz, 1H), 2.38 (ddd, J=14.4, 10.8, 5.7 Hz, 1H), 2.30 (dt, J=13.9, 4.8 Hz,1H), 1.87 (dt, J=15.3, 5.5 Hz, 1H), 1.77-1.60 (m, 5H), 1.38 (s, 9H); ¹³CNMR (126 MHz, CDCl₃) δ 214.9, 156.3, 144.9, 142.7, 128.6, 127.7, 126.7,118.3, 79.1, 54.0, 44.9, 39.8, 39.7, 34.4, 28.5, 27.2, 20.9; IR (NeatFilm, NaCl) 3463, 3374, 2975, 2935, 2865, 1713, 1703, 1699, 1505, 1455,1365, 1247, 1169 cm⁻¹; HRMS (FAB+) m/z calc'd for C₂₁H₃₀NO₃ [M+H]⁺:344.2226, found 344.2236; SFC conditions: 15% IPA, 2.5 mL/min, ChiralpakAD-H column, λ=210 nm, t_(R) (min): major=2.46, minor=2.78.

(S)-tert-Butyl (1-allyl-2-oxocycloheptyl)methylcarbamate (7b)

The reaction was conducted according to representative procedure B. Ketoester 6b (97.6 mg, 0.300 mmol). The reaction mixture was stirred at 23°C. for 20 h. Flash column chromatography (SiO₂, 10→15% EtOAc in hexanes)afforded ketone 7b (78.7 mg, 0.280 mmol, 93% yield) as a pale yellowoil. 87% ee, [α]_(D) ²⁵−22.7 (c 0.85, CHCl₃); R_(f)=0.53 (20% EtOAc inhexanes); ¹H NMR (500 MHz, CDCl₃) δ 5.72 (ddt, J=17.3, 10.4, 7.5 Hz,1H), 5.12-5.03 (m, 2H), 4.93 (brs, 1H), 3.31-3.19 (m, 2H), 2.65-2.56 (m,1H), 2.46 (ddd, J=11.3, 8.8, 2.5 Hz, 1H), 2.35 (m, 1H), 2.20 (m, 1H),1.79-1.41 (m, 8H), 1.41 (s, 9H); ¹³C NMR (126 MHz, CDCl₃) δ 217.1,156.2, 133.2, 118.8, 79.3, 54.8, 45.2, 41.1, 39.4, 33.3, 30.8, 28.5,26.7, 24.7; IR (Neat Film, NaCl) 3372, 2930, 1716, 1698, 1503, 1365,1247, 1117 cm⁻¹; HRMS (ESI+) m/z calc'd for C₁₇H₂₈NO₃ [M+H]⁺: 282.2064,found 282.2051; SFC conditions: 5% IPA, 2.5 mL/min, Chiralpak AD-Hcolumn, λ=210 nm, t_(R) (min): major=4.25, minor=4.63.

(S)-tert-Butyl (1-allyl-2-oxocyclopentyl)methylcarbamate (7c)

The reaction was conducted according to representative procedure B. Ketoester 6c (59.5 mg, 0.200 mmol). The reaction mixture was stirred at 23°C. for 20 h. Flash column chromatography (SiO₂, 10→15% EtOAc in hexanes)afforded ketone 7c (50.0 mg, 0.196 mmol, 98% yield) as a colorless oil.82% ee, [α]_(D) ²⁵−12.8 (c 0.96, CHCl₃); R_(f)=0.38 (25% EtOAc inhexanes); ¹H NMR (500 MHz, CDCl₃) δ 5.69 (ddt, J=17.4, 10.2, 7.4 Hz,1H), 5.14-5.05 (m, 2H), 4.86 (brs, 1H), 3.25 (dd, J=13.9, 6.9 Hz, 1H),3.14 (dd, J=13.9, 5.7 Hz, 1H), 2.30-2.23 (m, 2H), 2.20-2.13 (m, 2H),1.99-1.79 (m, 4H), 1.43 (s, 9H); ¹³C NMR (126 MHz, CDCl₃) δ 222.6,156.3, 133.0, 119.1, 79.5, 52.5, 44.0, 38.4, 37.5, 31.1, 28.5, 18.8; IR(Neat Film, NaCl) 3360, 2975, 1713, 1510, 1365, 1248, 1166 cm⁻¹; HRMS(ESI+) m/z calc'd for C₁₄H₂₃NO₃Na [M+Na]⁺: 276.1570, found 276.1565; SFCconditions: 5% IPA, 2.5 mL/min, Chiralpak AD-H column, λ=210 nm, t_(R)(min): major=2.97, minor=4.26.

(S)-tert-butyl((1-allyl-4-isobutoxy-2-oxocyclohept-3-en-1-yl)methyl)carbamate (7d)

The reaction was conducted according to representative procedure B. Ketoester 6d (100 mg, 0.253 mmol); [Pd₂(pmdba)₃] (13.9 mg, 0.012 mmol, 0.05equiv). The reaction mixture was stirred at 23° C. for 24 h. Flashcolumn chromatography (SiO₂, 10% EtOAc in hexanes) afforded ketone 7d(62.2 mg, 0.177 mmol, 70% yield) as a pale yellow oil. 92% ee, [α]_(D)²⁵−28.7 (c 0.65, CHCl₃); R_(f)=0.6 (25% EtOAc in hexanes); ¹H NMR (500MHz, CDCl₃) δ 5.70 (ddt, J=17.5, 10.3, 7.4 Hz, 1H), 5.28 (s, 1H),5.10-5.03 (m, 3H), 3.53-3.44 (m, 2H), 3.33 (dd, J=13.6, 6.4 Hz, 1H),3.18 (dd, J=13.6, 6.4 Hz, 1H), 2.55-2.42 (m, 2H), 2.37-2.28 (m, 2H),1.98 (dt, J=13.3, 6.7 Hz, 1H), 1.94-1.87 (m, 1H), 1.81-1.72 (m, 3H),1.41 (s, 9H), 0.95 (d, J=6.7 Hz, 6H); ¹³C NMR (126 MHz, CDCl₃) δ 205.8,172.7, 156.4, 133.4, 118.8, 104.9, 79.1, 74.7, 55.5, 47.1, 41.3, 36.1,31.6, 28.6, 28.0, 20.5, 19.3; IR (Neat Film, NaCl) 3373, 3075, 2972,2931, 2868, 1716, 1694, 1504, 1393, 1366, 1249, 1166 cm⁻¹; HRMS (FAB+)m/z calc'd for C₂₀H₃₄NO₄ [M+H]⁺: 352.2488, found 352.2474; SFCconditions: 3% IPA, 2.5 mL/min, Chiralpak AS-H column, λ=254 nm, t_(R)(min): major=4.41, minor=6.12.

(S)-tert-butyl((2-allyl-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)methyl)carbamate (7e)

The reaction was conducted according to representative procedure B. Ketoester 6e (81 mg, 0.225 mmol); [Pd₂(pmdba)₃] (12.3 mg, 0.011 mmol, 0.05equiv). The reaction mixture was stirred at 23° C. for 24 h. Flashcolumn chromatography (SiO₂, 10% EtOAc in hexanes) afforded ketone 7e(52.2 mg, 0.167 mmol, 74% yield) as a pale yellow oil. 93% ee, [α]_(D)²⁵−1.3 (c 1.32, CHCl₃); R_(f)=0.6 (25% EtOAc in hexanes); ¹H NMR (500MHz, CDCl₃) δ 8.00 (dd, J=8.0, 1.4 Hz, 1H), 7.48 (td, J=7.5, 1.5 Hz,1H), 7.30 (td, J=7.6, 1.2 Hz, 1H), 7.23 (d, J=7.6 Hz, 1H), 5.79 (m, 1H),5.15-5.05 (m, 3H), 3.50 (dd, J=13.9, 6.2 Hz, 1H), 3.29 (dd, J=13.9, 6.9Hz, 1H), 3.11 (ddd, J=16.9, 11.1, 5.3 Hz, 1H), 2.94 (dt, J=17.5, 4.6 Hz,1H), 2.37 (dd, J=14.2, 8.0 Hz, 1H), 2.28 (dd, J=14.2, 6.8 Hz, 1H), 2.11(ddd, J=14.0, 11.1, 5.2 Hz, 1H), 2.03 (dt, J=14.0, 4.7 Hz, 1H), 1.41 (s,9H); ¹³C NMR (126 MHz, CDCl₃) δ 202.2, 156.4, 143.5, 133.7, 132.7,131.6, 129.0, 127.9, 126.9, 119.2, 79.2, 49.3, 44.8, 36.6, 28.9, 28.5,25.0; IR (Neat Film, NaCl) 3449, 3378, 3073, 2976, 2930, 1716, 1699,1678, 1600, 1505, 1455, 1365, 1232, 1170 cm⁻¹; HRMS (FAB+) m/z calc'dfor C₁₉H₂₆NO₃ [M+H]⁺: 316.1913, found 316.1920; SFC conditions: 15% IPA,2.5 mL/min, Chiralpak AD-H column, λ=210 nm, t_(R) (min): major=2.48,minor=2.80.

(S)-tert-butyl ((3-allyl-1-benzyl-4-oxopiperidin-3-yl)methyl)carbamate(7f)

The reaction was conducted according to representative procedure B. Ketoester 6f (115 mg, 0.286 mmol); [Pd₂(pmdba)₃] (15.7 mg, 0.014 mmol, 0.05equiv). The reaction mixture was stirred at 23° C. for 24 h. Flashcolumn chromatography (SiO₂, 10% EtOAc in hexanes) afforded ketone 7f(79.3 mg, 0.223 mmol, 78% yield) as a pale yellow oil. 90% ee, [α]_(D)²⁵−34.0 (c 1.58, CHCl₃); R_(f)=0.55 (25% EtOAc in hexanes); ¹H NMR (500MHz, CDCl₃) δ 7.37-7.27 (m, 5H), 5.61 (m, 1H), 5.07 (m, 1H), 5.04 (d,J=1.1 Hz, 1H), 5.00 (m, 1H), 3.58 (d, J=13.0 Hz, 1H), 3.53 (d, J=13.0Hz, 1H), 3.37 (dd, J=14.0, 7.3 Hz, 1H), 3.19 (dd, J=14.0, 5.7 Hz, 1H),2.84 (m, 1H), 2.69 (d, J=11.6 Hz, 1H), 2.63-2.50 (m, 3H), 2.48-2.36 (m,3H), 1.41 (s, 9H); ¹³C NMR (126 MHz, CDCl₃) δ 212.8, 156.2, 138.3,132.6, 129.0, 128.5, 127.4, 119.2, 79.3, 62.3, 59.7, 53.6, 53.1, 44.1,39.5, 38.1, 28.5; IR (Neat Film, NaCl) 3452, 3373, 3063, 2976, 2929,2807, 1713, 1638, 1504, 1453, 1391, 1365, 1248, 1170 cm⁻¹; HRMS (FAB+)m/z calc'd for C₂₁H₃₁N₂O₃ [M+H]⁺: 359.2335, found 359.2345; SFCconditions: 8% IPA, 2.5 mL/min, Chiralpak AD-H column, λ=210 nm, t_(R)(min): major=4.94, minor=6.46.

(S)-tert-Butyl ((3-allyl-1-benzoyl-2-oxopiperidin-3-yl)methyl)carbamate(7g)

The reaction was conducted according to representative procedure B.Amido ester 6g (83.3 mg, 0.200 mmol). The reaction mixture was stirredat 40° C. for 20 h. Flash column chromatography (SiO₂, 15→20% EtOAc inhexanes) afforded lactam 7g (69.7 mg, 0.187 mmol, 94%) as a colorlessoil. 90% ee, [α]_(D) ²⁵+33.6 (c 1.05, CHCl₃); R_(f)=0.29 (25% EtOAc inhexanes); ¹H NMR (500 MHz, CDCl₃) δ 7.56-7.46 (m, 3H), 7.44-7.37 (m,2H), 5.78 (m, 1H), 5.24-5.15 (m, 2H), 4.96 (m, 1H), 3.84 (m, 1H), 3.73(ddd, J=12.7, 10.3, 4.3 Hz, 1H), 3.37 (dd, J=13.8, 6.5 Hz, 1H), 3.22(dd, J=13.8, 6.5 Hz, 1H), 2.60 (dd, J=13.8, 8.0 Hz, 1H), 2.48 (dd,J=13.8, 6.7 Hz, 1H), 2.12-1.93 (m, 3H), 1.82 (m, 1H), 1.42 (s, 9H); ¹³CNMR (126 MHz, CDCl₃) δ 178.6, 175.4, 156.4, 136.3, 131.9, 131.8, 128.4,127.6, 120.1, 79.5, 48.8, 47.2, 46.0, 39.7, 28.8, 28.5, 19.3; IR (NeatFilm, NaCl) 3373, 2975, 1693, 1678, 1502, 1390, 1365, 1272, 1248, 1167cm⁻¹; HRMS (ESI+) m/z calc'd for C₂₁H₂₈N₂O₄Na [M+Na]⁺: 395.1941, found395.1954; SFC conditions: 10% MeOH, 3.0 mL/min, Chiralpak AD-H column,λ=254 nm, t_(R) (min): major=2.64, minor=3.12.

(R)-tert-Butyl ((2-allyl-4-benzoyl-3-oxomorpholin-2-yl)methyl)carbamate(7h)

The reaction was conducted according to representative procedure B.Morpholinone 6h (33.0 mg, 0.079 mmol). The reaction mixture was stirredat 40° C. for 12 h. Flash column chromatography (SiO₂, 15→20% EtOAc inhexanes) afforded morpholinone 7h (27.3 mg, 0.073 mmol, 92%) as acolorless oil. 99% ee, [α]_(D) ²⁵+10.8 (c 0.93, CHCl₃); R_(f)=0.43 (33%EtOAc in hexanes); ¹H NMR (500 MHz, CDCl₃) δ 7.57-7.48 (m, 3H),7.43-7.38 (m, 2H), 5.89 (m, 1H), 5.23-5.17 (m, 2H), 4.88 (br s, 1H),4.14-3.88 (m, 4H), 3.63 (m, 1H), 3.40 (dd, J=14.1, 5.6 Hz, 1H), 2.69(dd, J=14.3, 7.4 Hz, 1H), 2.52 (dd, J=14.3, 7.0 Hz, 1H), 1.44 (s, 9H);¹³C NMR (126 MHz, CDCl₃) δ 173.0, 172.6, 155.9, 135.6, 132.1, 131.7,128.3, 128.1, 119.9, 82.2, 79.9, 60.6, 46.0, 45.5, 40.0, 28.5; IR (NeatFilm, NaCl) 3382, 2978, 1707, 1689, 1509, 1367, 1281, 1250, 1225, 1166,1091 cm⁻¹; HRMS (ESI+) m/z calc'd for C₂₀H₂₆N₂O₅Na [M+Na]⁺: 397.1734,found 397.1728; SFC conditions: 3% MeOH, 2.5 mL/min, Chiralpak AS-Hcolumn, λ=254 nm, t_(R) (min): major=4.06, minor=4.62.

(S)-tert-butyl((3-allyl-4-oxo-9-tosyl-2,3,4,9-tetrahydro-1H-carbazol-3-yl)methyl)carbamate(7i)

The reaction was conducted according to representative procedure B. Ketoester 6i (100 mg, 0.181 mmol); [Pd₂(pmdba)₃] (10.0 mg, 0.009 mmol, 0.05equiv). The reaction mixture was stirred at 40° C. for 48 h. Flashcolumn chromatography (SiO₂, 10% EtOAc in hexanes) afforded ketone 7i(46.9 mg, 0.091 mmol, 51% yield) as a white foam. 92% ee, [α]_(D)²⁵−13.3 (c 0.28, C₆H₆); R_(f)=0.45 (25% EtOAc in hexanes); ¹H NMR (500MHz, CDCl₃) δ 8.20 (m, 1H), 8.16 (dd, J=7.3, 1.8 Hz, 1H), 7.77 (d, J=8.4Hz, 2H), 7.41-7.31 (m, 2H), 7.28 (m, 2H), 5.77 (m, 1H), 5.11 (m, 1H),5.08 (dd, J=17.1, 1.8 Hz, 1H), 5.05 (br t, J=6.7 Hz, 1H), 3.49 (dd,J=13.9, 6.2 Hz, 1H), 3.44 (dt, J=19.2, 4.8 Hz, 1H), 3.33-3.28 (m, 1H),3.27 (dd, J=13.9, 7.0 Hz, 1H), 2.38 (s, 3H), 2.32-2.28 (m, 2H),2.16-2.11 (m, 2H), 1.40 (s, 9H); ¹³C NMR (126 MHz, CDCl₃) δ 199.1,156.4, 150.1, 146.1, 136.4, 135.6, 132.9, 130.5, 126.8, 126.0, 125.6,125.1, 121.9, 119.3, 116.6, 114.1, 79.4, 49.4, 44.6, 37.5, 29.5, 28.5,21.8, 21.6; IR (Neat Film, NaCl) 3432, 3372, 3058, 2976, 2928, 1712,1657, 1505, 1451, 1407, 1366, 1247, 1173 cm⁻¹; HRMS (ESI+) m/z calc'dfor C₂₈H₃₃N₂O₅S [M+H]⁺: 509.2105, found 509.2094; SFC conditions: 15%IPA, 2.5 mL/min, Chiralcel OB-H column, λ=210 nm, t_(R) (min):major=7.21, minor=5.19.

TABLE 2 Two-step Synthesis of α-Aminomethyl Carbonyl Compounds fromβ-Oxo Esters.^(a)

6a 79% yield 6b 72% yield 6c 86% yield 7a 91% yield, 90% ee^(b,c) 7b 93%yield, 87% ee 7c 98% yield, 82% ee

6d 83% yield 6e 99% yield 6f 80% yield 7d 70% yield, 92% ee^(b) 7e 74%yield, 93% ee^(b) 7f 78% yield, 90% ee^(b)

6g 74% yield 6h 80% yield 6i 80% yield 7g 94% yield, 90% ee^(d) 7h 92%yield, 99% ee^(d) 7i 51% yield, 92% ee^(b,d) ^(a)Reaction conditions forstep 2: 6 (1 equiv), Pd₂(dba)₃ (5 mol %) and L1 (12.5 mol %) in toluene(0.033 M) at 23° C. for 12-48 h. ^(b)Pd₂(pmdba)₃ (pmdba =bis(4-methoxybenzylidene)acetone) was used instead of Pd₂(dba)₃.^(c)Enantiomeric excesses were determined by chiral SFC analysis.^(d)Reactions were performed on 6f, 6h, and 6i at 40° C.

As outlined in Table 2, a broad range of ketones and amides (e.g., 5)can easily be converted into enantioenriched tetrasubstitutedMannich-type products (e.g., 7a-i) with this two-step strategy. For allsubstrates, the first step proceeded in good to excellent yields(72-99%). In the allylic alkylation, 2-phenyl-2-propenyl-substituted 7awas obtained in high yield (91%) and excellent enantioselectivity (90%ee). Cycloheptanone 6b proved to be a good substrate and thecorresponding α-quaternary cycloheptanone 7b was isolated in 93% yieldand 87% ee, while cyclopentanone 6c gave slightly lowerenantioselectivity (82% ee). Vinylogous ester 6d and tetralone 6eafforded α-quaternary vinylogous ester 7d and tetralone 7e in 70% yieldand 92% ee, and 74% yield and 93% ee, respectively. Heterocyclic ketonescaffolds were found to be competent substrates for this transformation,as 4-piperidinone 7f was isolated in 78% yield and 90% ee. Lastly, wewere pleased to find that under slightly elevated reaction temperatures(40° C.), the desired lactam 7g, morpholinone 7h, and carbazolone 7iwere obtained in moderate to excellent yields (51-94%) and excellentenantioselectivities (90-99% ee).

Example 3. Methods for Determining Enantiomeric Excess and OpticalRotation of Alkylation Products

TABLE S-1 entry compound analytic conditions ee (%) polarimetry 1

SFC: 5% IPA, 2.5 mL/min Chiralpak AD-H, λ = 210 nm t_(R) (min): major3.73, minor 4.30 86 [α]_(D) ²⁵ − 25.5 (c 0.865, C₆H₆) 4a 2

SFC: 5% IPA, 2.5 mL/min Chiralpak AD-H, λ = 210 nm t_(R) (min): major8.12, minor 9.06 86 [α]_(D) ²⁵ − 38.6 (c 1.20, CHCl₃) 4b 3

SFC: 10% IPA, 2.5 mL/min Chiralcel OB-H, λ = 210 nm t_(R) (min): major9.47, minor 11.13 83 [α]_(D) ²⁵ − 29.3 (c 0.76, CHCl₃) 4c 4

SFC: 10% IPA, 2.5 mL/min Chiralcel OB-H, λ = 210 nm t_(R) (min): major6.53, minor 8.13 77 [α]_(D) ²⁵ − 28.9 (c 0.40, CHCl₃) 4d 5

SFC: 10% IPA, 2.5 mL/min Chiralpak AS-H, λ = 210 nm t_(R) (min): major6.94, minor 8.24 77 [α]_(D) ²⁵ − 27.4 (c 0.78, CHCl₃) 4e 6

SFC: 20% IPA, 2.5 mL/min Chiralpak AD-H, λ = 210 nm t_(R) (min): major4.04, minor 4.91 56 Specific Rotation Not Determined 4f 7

SFC: 15% IPA, 2.5 mL/min Chiralcel OJ-H, λ = 210 nm t_(R) (min): major3.14, minor 3.85 24 Specific Rotation Not Determined 4g

TABLE S-2 entry compound analytic conditions ee (%) polarimetry 1

SFC: 15% IPA, 2.5 mL/min Chiralpak AD-H, λ = 210 nm t_(R) (min): major2.46, minor 2.78 90 [α]_(D) ²⁵ − 30.87 (c 4.45, CHCl₃) 7a 2

SFC: 5% IPA, 2.5 mL/min Chiralpak AD-H, λ = 210 nm t_(R) (min): major4.25, minor 4.63 87 [α]_(D) ²⁵ − 22.7 (c 0.85, CHCl₃) 7b 3

SFC: 5% IPA, 2.5 mL/min Chiralpak AD-H, λ = 210 nm t_(R) (min): major2.97, minor 4.26 82 [α]_(D) ²⁵ − 12.8 (c 0.96, CHCl₃) 7c 4

SFC: 3% IPA, 2.5 mL/min Chiralpak AS-H, λ = 254 nm t_(R) (min): major4.41, minor 6.12 92 [α]_(D) ²⁵ − 28.7 (c 0.65, CHCl₃) 7d 5

SFC: 15% IPA, 2.5 mL/min Chiralpak AD-H, λ = 210 nm t_(R) (min): major2.48, minor 2.80 93 [α]_(D) ²⁵ − 1.3 (c 1.32, CHCl₃) 7e 6

SFC: 8% IPA, 2.5 mL/min Chiralpak AD-H, λ = 210 nm t_(R) (min): major4.94, minor 6.46 90 [α]_(D) ²⁵ − 34.0 (c 1.58, CHCl₃) 7f 7

SFC: 10% MeOH, 3.0 mL/min Chiralpak AD-H, λ = 254 nm t_(R) (min): major2.64, minor 3.12 90 [α]_(D) ²⁵ + 33.6 (c 1.05, CHCl₃) 7g 8

SFC: 3% MeOH, 2.5 mL/min Chiralpak AS-H, λ = 254 nm t_(R) (min): major4.06, minor 4.62 99 [α]_(D) ²⁵ + 10.8 (c 0.93, CHCl₃) 7h 9

SFC: 15% IPA, 2.5 mL/min Chiralcel OB-H, λ= 210 nm t_(R) (min): major7.21, minor 5.19 92 [α]_(D) ²⁵ − 13.3 (c 0.28, C₆H₆) 7i

Example 4. Total Synthesis of (−)-Isonitramine and (+)-Sibirinine

In order to exhibit the utility of our method for generating interestingand useful chiral building blocks, the first total synthesis of(+)-sibirinine (12) was carried out using β-keto ester 3b as ourstarting material (Scheme 2). Asymmetric allylic alkylation using onegram of 3b proceeded with one half of the typical catalyst loadingwithout any loss of enantioselectivity. Reduction of β-amino ketone 4bwith diisobutylaluminum hydride (DIBAL), followed by acetylation of theresulting alcohol, yielded carbamate 8 as a single diastereomer.Hydroboration of the terminal alkene in carbamate 8 provided primaryalcohol 9 in 86% yield over 3 steps. Cyclization of the mesylate derivedfrom primary alcohol 9 smoothly delivered spirocycle 10. Removal of theacetyl and Cbz groups using potassium hydroxide furnished(−)-isonitramine (11) in 77% yield. Treatment of (−)-isonitramine 11with excess acetaldehyde yielded the desired hemiaminal, which wassmoothly oxidized by m-CPBA to give (+)-sibirinine (12) in 92% yieldover two steps. Notably, conversion of (−)-isonitramine to(+)-sibirinine can be accomplished in one pot by forming the hemiaminalintermediate under an oxygen atmosphere, albeit in diminished yield.Spectral data of 11 and 12 were identical to those previously reported.Our synthesis of (−)-isonitramine confirms the absolute stereochemistryof 4b.

Synthesis of Alcohol 9

To a solution of enantioenriched ketone 4b (851 mg, 2.82 mmol) in CH₂Cl₂(14.2 mL) was added DIBAL (6.21 mL, 1.0 M solution in CH₂Cl₂, 6.21 mmol,2.20 equiv) dropwise at −78° C. After stirring at −78° C. for 15 min,the reaction mixture was quenched with saturated aqueous Rochelle's salt(20 mL) and stirred at 23° C. for 2 h. The phases were separated and theaqueous phase was extracted with CH₂Cl₂ (2×25 mL). The combined organicphases were dried over Na₂SO₄, filtered, and concentrated under reducedpressure. The crude product was used for the next reaction withoutfurther purification.

To a solution of the crude alcohol in Ac₂O (7.1 mL) was added pyridine(7.1 mL) at room temperature. After full consumption of the startingmaterial was observed by TLC analysis, the reaction mixture wasconcentrated and azeotropically dried with toluene twice. The resultingresidue was used in the next reaction without further purification.

To a flame-dried flask was added cyclohexene (1.43 mL, 14.1 mmol, 5.00equiv), diethyl ether (10 mL), and BH₃.Me₂S (7.05 mL, 2.0 M solution inTHF, 3.5 mmol, 1.24 equiv) at 0° C. The reaction mixture was stirred at0° C. for 3 h, then the solid was allowed to settle without stirring,and the supernatant was removed using a syringe. To the resulting solidwas added THF (8.0 mL) and a solution of acetate 8 in THF (6.2 mL) at 0°C. After full consumption of acetate 8 by TLC analysis, the reactionmixture was quenched with NaBO₃ (3.25 g, 21.2 mmol, 7.52 equiv) and H₂O(14 mL) and stirred at room temperature for 1 h. The reaction mixturewas diluted with EtOAc, the phases were separated, and the aqueous phasewas extracted with EtOAc (2×25 mL). The combined organic phases weredried over Na₂SO₄, filtered, and concentrated under reduced pressure.Flash column chromatography (SiO₂, 30→50% EtOAc in hexanes) affordedalcohol 9 (886 mg, 86% yield, over 3 steps) as a colorless oil. [α]_(D)²⁵+7.5 (c 0.95, CHCl₃); R_(f)=0.33 (50% EtOAc in hexanes); ¹H NMR (500MHz, CDCl₃) δ 7.39-7.28 (m, 5H), 5.35 (m, 1H), 5.14-5.02 (m, 2H), 4.77(dd, J=9.7, 4.5 Hz, 1H), 3.68-3.58 (m, 2H), 3.30 (dd, J=14.3, 8.0 Hz,1H), 2.88 (dd, J=14.2, 5.5 Hz, 1H), 2.05 (s, 3H), 1.71-1.16 (m, 12H);¹³C NMR (126 MHz, CDCl₃) δ 171.4, 157.1, 136.7, 128.6, 128.3, 128.2,75.3, 66.9, 63.5, 45.5, 40.9, 30.0, 26.9, 26.0, 25.3, 23.9, 21.4, 20.4;IR (Neat Film, NaCl) 3385, 2937, 2866, 1718, 1528, 1455, 1374, 1247,1026 cm⁻¹; HRMS (ESI+) m/z calc'd for C₂₀H₃₀NO₅ [M+H]⁺: 364.2118, found364.2109.

Synthesis of Spiroamine 10

To a solution of primary alcohol 9 (865 mg, 2.38 mmol) in CH₂Cl₂ (12 mL)was added Et₃N (0.497 mL, 3.57 mmol, 1.50 equiv) and MsCl (0.203 mL,2.63 mmol, 1.10 equiv) at 0° C. After full consumption of alcohol 9 wasobserved by TLC analysis, the reaction mixture was quenched withsaturated aqueous NaHCO₃ (25 mL) and the phases were separated. Theaqueous phase was extracted with CH₂Cl₂ (2×25 mL). The combined organicphases were dried over Na₂SO₄, filtered, and concentrated under reducedpressure. The crude product was used in the next reaction withoutfurther purification.

To a suspension of sodium hydride (114 mg, 60 wt % dispersion in mineraloil, 2.86 mmol) in THF (6 mL) was added a solution of the abovemethanesulfonate in THF (6 mL) at 0° C. The reaction mixture was stirredat reflux for 2 h. Upon cooling to 23° C., the reaction mixture wasquenched with saturated aqueous NH₄Cl (20 mL) and diluted with CH₂Cl₂(20 mL). The phases were separated, and the aqueous phase was extractedwith CH₂Cl₂ (3×25 mL). The combined organic phases were dried overNa₂SO₄, filtered, and concentrated under reduced pressure. Flash columnchromatography (SiO₂, 15% EtOAc in hexanes) afforded spirocycliccarbamate 10 (732 mg, 89% yield, over 2 steps) as a colorless oil.[α]_(D) ²⁵+46.8 (c 0.97, CHCl₃); R_(f)=0.57 (33% EtOAc in hexanes); ¹HNMR (500 MHz, CDCl₃, mixture of rotamers) δ 7.39-7.26 (m, 5H), 5.20-5.01(m, 2H), 4.86-4.61 (m, 1H), 3.96-2.91 (m, 4H), 2.05 (s, 3H), 1.87-1.00(m, 12H); ¹³C NMR (126 MHz, CDCl₃, mixture of rotamers) δ 170.6, 155.7,137.0, 128.6, 128.1, 128.0, 75.2 (74.3), 67.2, 51.4 (50.7), 44.8, 37.0(36.9), 30.6 (29.1), 30.2, 26.5, 22.4 (21.8), 21.3, 20.8 (20.7), 20.6(20.5); IR (Neat Film, NaCl) 2938, 2861, 1732, 1699, 1434, 1242 cm⁻¹;HRMS (ESI+) m/z calc'd for C₂₀H₂₉NO₄ [M+H]⁺: 346.2013, found 346.2016.

Synthesis of (−)-isonitramine (11)

To a solution of spirocyclice carbamate 10 (712 mg, 2.06 mmol) inethylene glycol (13 mL) was added KOH (3.00 g, 53.4 mmol, 25.92 equiv)and hydrazine hydrate (0.51 mL) at 23° C. After stirring at 120° C. for1.5 h, the reaction mixture cooled to 23° C. and diluted with H₂O (100mL). The aqueous phase was extracted with CH₂Cl₂ (200 mL) using acontinuous liquid/liquid extractor and the organic phase wasconcentrated under reduced pressure. Flash column chromatography (SiO₂,CHCl₃:MeOH:NH₃(aq)=46:50:4 eluent) afforded (−)-isonitramine (11) (270mg, 77% yield) as a white solid. [α]_(D) ²⁵−4.1 (c 0.96, CHCl₃); Lit:[α]_(D) ²⁰−5.0 (c 2.1, CHCl₃); R_(f)=0.30 (CHCl₃:MeOH:NH₃(aq)=46:50:4);m.p. 86.9-88.8° C.; ¹H NMR (500 MHz, CDCl₃) δ 3.66 (dd, J=11.3, 3.7 Hz,1H), 3.04 (m, 1H), 2.94 (m, 1H), 2.60 (ddd, J=11.3, 11.3, 3.4 Hz, 1H),2.52 (d, J=11.3 Hz, 1H), 2.24 (m, 1H), 2.06 (m, 1H), 1.78-1.14 (m, 8H),1.06 (ddd, J=13.3, 13.3, 5.5 Hz, 1H), 0.96 (m, 1H); ¹³C NMR (126 MHz,CDCl₃) δ 80.7, 61.0, 47.4, 36.9, 36.3, 29.9, 29.0, 24.4, 23.3, 20.4; IR(Neat Film, NaCl) 3292, 2929, 2858, 1539, 1457, 1419, 1282, 1064 cm⁻¹;HRMS (ESI+) m/z calc'd for C₁₀H₂₀NO [M+H]⁺: 170.1539, found 170.1541.

Synthesis of (+)-sibirinine (12)

An oven-dried 1-dram vial was charged with a magnetic stirring bar, 11(20 mg, 0.118 mmol), powdered 3 Å molecular sieves (40 mg), and CH₂Cl₂(1.5 mL). To this stirring suspension was added acetaldehyde (0.133 mL,2.36 mmol, 20.0 equiv). The vial was sealed with a teflon cap, and thereaction was stirred at 23° C. for 30 h. The reaction mixture was thenfiltered through celite, washing with CH₂Cl₂. The filtrate wasconcentrated under reduced pressure to yield a pale yellow oil, whichwas used in the subsequent reaction without further purification.

The above crude hemiaminal was dissolved in CH₂Cl₂ (1.2 mL) and cooledto 0° C. (water/ice bath). To this stirring solution was added m-CPBA(29 mg, 0.13 mmol) in one portion. After 15 min, full consumption ofstarting material was observed by TLC analysis. The reaction mixture wasfiltered through celite, washing with CH₂Cl₂, and concentrated underreduced pressure. Flash column chromatography (SiO₂, CH₂Cl₂:NH₃ (7Nsolution in MeOH)=92:8 eluent) afforded (+)-sibirinine (12) (22.9 mg,92% yield, over 2 steps) as a colorless oil. [α]_(D) ²⁵+10.3 (c 0.56,CHCl₃); R_(f)=0.40 (CH₂Cl₂:NH₃ (7N solution in MeOH)=9:1); ¹H NMR (500MHz, CDCl₃) δ 4.50 (qd, J=5.8, 1.5 Hz, 1H), 3.73 (dd, J=13.4, 7.1 Hz,1H), 3.53 (ddd, J=12.0, 4.1, 1.5 Hz, 1H), 3.21 (d, J=12.2 Hz, 1H), 3.11(dt, J=12.2, 2.5 Hz, 1H), 3.03 (dddd, J=14.7, 13.4, 5.5, 1.6 Hz, 1H),2.45 (tdt, J=14.4, 13.5, 5.9 Hz, 1H), 2.32 (dd, J=14.1, 5.8 Hz, 1H),1.87 (dtd, J=13.1, 3.8, 1.7 Hz, 1H), 1.79 (dq, J=12.3, 3.6 Hz, 1H), 1.65(d, J=5.8 Hz, 3H), 1.64-1.60 (m, 1H), 1.57-1.46 (m, 2H), 1.46 (dt,J=13.0, 4.0 Hz, 1H), 1.41-1.31 (m, 2H), 1.23 (m, 1H), 1.17 (m, 1H); ¹³CNMR (126 MHz, CDCl₃) δ 102.2, 84.4, 77.8, 62.5, 38.2, 34.7, 27.0, 26.3,24.7, 21.2, 19.6, 14.6; IR (Neat Film, NaCl) 2934, 2854, 1466, 1446,1367, 1138, 1120, 1103, 961, 940 cm⁻¹; HRMS (ESI/APCI) m/z calc'd forC₁₂H₂₂NO₂ [M+H]⁺: 212.1645, found 212.1640.

INCORPORATION BY REFERENCE

All publications and patents mentioned herein are hereby incorporated byreference in their entirety as if each individual publication or patentwas specifically and individually indicated to be incorporated byreference. In case of conflict, the present application, including anydefinitions herein, will control.

EQUIVALENTS

While specific embodiments of the subject invention have been discussed,the above specification is illustrative and not restrictive. Manyvariations of the invention will become apparent to those skilled in theart upon review of this specification and the claims below. The fullscope of the invention should be determined by reference to the claims,along with their full scope of equivalents, and the specification, alongwith such variations.

1-63. (canceled)
 64. A method comprising: preparing a compound offormula (Ia):

the preparing the compound of formula (Ia) comprising treating acompound of formula (IIa):

with a transition metal catalyst under alkylation conditions, wherein,as valence and stability permit, A, B, C, and D each independentlyrepresent, as valence permits, NR′, CR″R′″, C(O), O, S, CR″, or N;provided that at least one occurrence of A, B, C, and D is NR′ and atleast one occurrence of the remaining A, B, C, and D is NR′ or O; andprovided that no two adjacent occurrences of A, B, C, and D are NR′, O,S, or N; R′ represents hydrogen or optionally substituted alkyl,cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,alkenyl, alkynyl, —C(O)alkyl, —C(O)aryl, —C(O)aralkyl, —C(O)heteroaryl,—C(O)heteroaralkyl, —C(O)O(alkyl), —C(O)O(aryl), —C(O)O(aralkyl),—C(O)O(heteroaryl), —C(O)O(heteroaralkyl), —S(O)₂(aryl), —S(O)₂(alkyl),—S(O)₂(haloalkyl), —OR¹⁴, —SR¹⁴, or —NR¹⁴R¹⁵; R″ and R′″ eachindependently represent hydrogen, hydroxyl, halogen, nitro, alkyl,cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,(heterocycloalkyl)alkyl, heterocycloalkyl, alkenyl, alkynyl, cyano,carboxyl, sulfate, amino, alkoxy, aryloxy, alkylamino, alkylthio,hydroxyalkyl, alkoxyalkyl, aminoalkyl, thioalkyl, ether, thioether,ester, amide, thioester, carbonate, carbamate, urea, sulfonate, sulfone,sulfoxide, sulfonamide, acyl, acyloxy, or acylamino; or any twooccurrences of R′, R″, and R′− on adjacent A, B, C, or D groups, takentogether with the intervening atoms, form an optionally substitutedaryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, orheterocycloalkenyl group; each occurrence of

independently represents a double bond or a single bond as permitted byvalence; m and n are integers each independently selected from 0, 1, and2, wherein the sum of m and n is 1, 2, 3, or 4; R^(1a) and R^(1b) eachindependently represent hydrogen or optionally substituted alkyl,cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,alkenyl, alkynyl, —C(O)alkyl, —C(O)aryl, —C(O)aralkyl, —C(O)heteroaryl,—C(O)heteroaralkyl, —C(O)O(alkyl), —C(O)O(aryl), —C(O)O(aralkyl),—C(O)O(heteroaryl), —C(O)O(heteroaralkyl), —S(O)₂(aryl), —S(O)₂(alkyl),—S(O)₂(haloalkyl), —OR¹⁴, —SR¹⁴, or —NR¹⁴R¹⁵; R² and R³ eachindependently represent hydrogen or substituted or unsubstituted alkyl,aralkyl, aryl, heteroaralkyl, heteroaryl, (cycloalkyl)alkyl, cycloalkyl,(heterocycloalkyl)alkyl, heterocycloalkyl, alkenyl, alkynyl, alkylamino,hydroxyalkyl, alkoxyalkyl, aminoalkyl, or thioalkyl; R⁴, R⁵, R⁶, R⁷, R⁸,R⁹, R¹⁰, and R¹¹ are each independently selected for each occurrencefrom hydrogen, hydroxyl, halogen, nitro, alkyl, alkenyl, alkynyl, cyano,carboxyl, sulfate, amino, alkoxy, alkylamino, alkylthio, hydroxyalkyl,alkoxyalkyl, aminoalkyl, thioalkyl, ether, thioether, ester, amide,thioester, carbonate, carbamate, urea, sulfonate, sulfone, sulfoxide,sulfonamide, acyl, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl,heterocycloalkyl, aralkyl, arylalkoxy, heteroaralkyl, (cycloalkyl)alkyl,and (heterocycloalkyl)alkyl; and R¹⁴ and R¹⁵ are independently selectedfor each occurrence from hydrogen or substituted or unsubstituted alkyl,aralkyl, aryl, heteroaralkyl, heteroaryl, (cycloalkyl)alkyl, cycloalkyl,(heterocycloalkyl)alkyl, heterocycloalkyl, alkenyl, and alkynyl, whereinthe compound represented by formula (Ia) has about 70% ee or greater;and synthesizing a biologically active product from the compound offormula (Ia).
 65. The method of claim 64, wherein the transition metalcatalyst comprises a transition metal selected from palladium, nickel,and platinum.
 66. The method of claim 64, wherein the transition metalcatalyst further comprises a chiral ligand.
 67. The method of claim 64,wherein the compound represented by formula (Ia) has about 80% ee orgreater.
 68. The method of claim 64, wherein the compound represented byformula (Ia) has about 85% ee or greater.
 69. The method of claim 64,wherein the compound represented by formula (Ia) has about 90% ee orgreater.